JPH0625181A - Fused five-membered heterocyclic compounds, their preparation and pharmaceutical preparations containing said compounds - Google Patents

Abstract

PURPOSE: To obtain new compounds having coagulation-inhibiting action.

CONSTITUTION: Compounds of formula I [R₁ is H, F, Cl, an alkyl or the like; X is O, S, N or the like; Y is NO, N or the like; Z₁-Z₄ are each methylene, C, imino or the like, one or more of Z₁-Z₄ should contain C, Z₅ and Z₆ are each C, or one of them is N and the other is C; A is cyano, amino or the like; B is phenylene (optionally substd. with F, alkyl or the like) or the like; C is a bond, alkylene or the like; D is a bond or alkylene; E is a 1-7C alkylene or the like; F is a bond, 1-6C alkylene or the like; G is carbonyl not bonded to a hetero atom of E or the like], their tautomers, their stereoisomers and their mixing compounds and their salts, such as 2-(4-amidino-phenyl)-5-(2-carboxy- ethyl)-amino-carbonyl]-1-methyl-benzoimidazole. The compd. of the formula I is obtained, for example, by hydrolyzing a compd. of formula II (G¹ is bonded to C) in the presence of an acid such as hydrochloric acid in a solvent such as water and methanol at a temp. of -10 to 120°C.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to fused 5-membered heterocyclic compounds, a process for their preparation and pharmaceutical preparations containing these compounds.

[0002]

The present invention has the general formula:

[0003]

[Chemical 18]

A fused 5-membered heterocyclic compound, a tautomer,
Stereoisomers, including their mixtures, and their salts, especially their physiologically acceptable salts with inorganic or organic acids or bases, which have, inter alia, valuable pharmacological properties, preferably an aggregation-inhibiting effect. ), Pharmaceutical compositions containing these compounds and methods for their preparation. In the above general formula I, R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; an alkyl group, an aralkyl group, an aryl group, a heteroaryl group, an R ₃ O- group, a (R ₃ ) ₂ N- Base,
R ₄ CO-NR ₃ - group, alkylsulfonyl -NR ₃ - represents a group or R ₅ groups, - groups, arylsulfonyl -NR ₃ - group, R ₃ S- group, R ₃ SO- group, R ₃ SO ₂ (In the formula, R ₃ represents a hydrogen atom, a C _1-6 alkyl group, an aryl group, a heteroaryl group, an aralkyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group, and R ₄ represents a hydrogen atom; An alkyl group or an alkoxy group having a carbon atom; 1 to 6 in an aryl group, a heteroaryl group or an alkyl moiety
Represents an aralkyl group having 4 carbon atoms, and R ₅ represents an azetidino group, a pyrrolidino group, a hexamethyleneimino group, a heptamethyleneimino group or a piperidino group, and a methylene group at the 4-position is an oxygen atom; a sulfenyl group,
A sulfinyl group or a sulfonyl group; or an R ₃ group,
R ₄ CO- group, optionally substituted by an imino group substituted by an alkylsulfonyl or arylsulfonyl group, wherein R ₃ and R ₄ are as defined above.

X is an oxygen atom, a sulfur atom or a nitrogen atom
Or-NR₂Represents a group (in the formula, R₂Is a hydrogen atom; straight chain
Or branch C_1-15Alkyl group; straight or branched C_3-10A
Lucenyl or alkynyl groups (with their double bond or
Heavy bonds must not be directly attached to nitrogen atoms);
A cycloalkyl moiety having 3 to 7 carbon atoms
Chroalkyl group or cycloalkylalkyl group; Ali
Group or heteroaryl group; C_2-6Alkyl group (this
Is-NR₂-From the β-position to the nitrogen atom of the group R ₃O-group, (R
₃)₂N- group, R_FourCO-NR₃-Group, alkylsulfonyl-NR₃-
Group, arylsulfonyl-NR₃-Group, alkylsulfeni
Group, alkylsulfinyl group, alkylsulfonyl group
Or R_FiveSubstituted by a group); or C_1-6Al
Kill group (which may be one or two aryl groups; heteroaryl
Reel base, R₆OCO-group, (R₃)₂NCO- group, R_FiveCO-based, R₃O-
CO- Alkylene-NR₃-CO- group, (R₃)₂N-CO-alkylene-NR₃
-CO- group or R_FiveCO- Alkylene-NR₃-CO- group (in the formula, R
₃And R_FiveIs as defined above, and R₆Is
Hydrogen atom, C_1-6Alkyl group, C_5-7Cycloalkyl group
Represents an aralkyl group)
You)

Y represents an NO group, a nitrogen atom or a methine group which may be optionally substituted with alkyl, and Z ₁ , Z
₂ , Z ₃ and Z ₄ (which may be the same or different) represent a methine group, a carbon atom, an imino group or a nitrogen atom, and at least one of the groups Z _{1 to} Z ₄ is It must contain a carbon atom, and one or two methine groups adjacent to the nitrogen atom may be substituted by a carbonyl group, Z ₅ and Z ₆ each represent a carbon atom,
Or one of the groups Z ₅ or Z ₆ represents a nitrogen atom and the other group of the groups Z ₅ or Z ₆ represents a carbon atom, A being a cyano group; an amino group; a straight-chain or branched C _1-4 Aminoalkyl group, which represents an amidino group, a guanidino group or a guanidinoalkyl group, wherein one or two of the nitrogen atoms in the above amino group, aminoalkyl group, amidino group, guanidino group or guanidinoalkyl group The hydrogen atom may be substituted by one or two C _1-4 alkyl groups, or the hydrogen atom may be a C _2-5 (alkoxycarbonyl) group; C _4-6 (alkenyloxycarbonyl) group; C _{2 -Five}
(Alkylcarbonyl) group; arylcarbonyl group, aryloxycarbonyl group, aralkoxycarbonyl group, alkanoyloxymethoxy-carbonyl group, cycloalkanoyloxymethoxycarbonyl group, aralkanoyloxymethoxycarbonyl group, aroyloxymethoxycarbonyl group, It may be substituted by a phosphono group, a dialkylphosphoryl group or an O-alkyl-phosphono group, the alkanoyl moieties may each contain from 2 to 7 carbon atoms, and the cycloalkanoyl moieties are each from a total of 4 to 8 carbon atoms. The methoxy moieties may each be substituted by a C _3-6 cycloalkyl group; an aralkyl group, an aryl group or an alkyl group; or two alkyl groups, each of which may also be substituted with a methylene carbon atom. A five-membered ring Or may form a 6-membered ring, or when B represents a cyclic imine having 4 to 5 ring members, A also represents a hydrogen atom or an alkyl group (each of which is bonded to an imino nitrogen). Is displayed),

B is a phenylene group (which is a fluorine atom, a chlorine atom or a bromine atom; an alkyl group, a hydroxy group,
Monosubstituted or disubstituted with an alkoxy group, an alkylsulfenyl group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a trifluoromethyl group. And these substituents may be the same,
May be different, and at the same time, 1 or 2 methine groups in the above phenylene group may be substituted by 1 or 2 nitrogen atoms), or B is C
_3-7 cycloalkylene group (in a _4- or 5-membered cycloalkylene ring, one ring member may represent a nitrogen atom,
Also, in a 6- or 7-membered cycloalkylene ring, one or two ring members may each represent a nitrogen atom, while at the same time the bond to the carbon atom of the adjacent group is by such an optionally present nitrogen atom. May be carried out), indanylene group or 1,2,3,4-tetrahydronaphthylene group (its saturated ring is bound to group A, and its aromatic ring is bound to group C or a fused 5-membered heterocyclic group) Is displayed)

C is a bond, an alkylene group, an arylene group,
-O-alkylene group, -S-alkylene group, -NH-alkylene group, -N (alkyl) -alkylene group, -alkylene-NH- group, -alkylene-N (alkyl)-
Group, -SO- alkylene group or -SO ₂ - alkylene group, D is a bond or represents an alkylene group, E is C
_1-7 alkylene group, each represents an alkenylene group or alkynylene group having 2 to 7 carbon atoms, the double bond or triple bond of which is a nitrogen atom of -Z ₁ -Z ₂ -Z ₃ -Z ₄ -group It may not be directly bonded, or E may be -Z ₁ -Z
₂ -Z ₃ -Z ₄ - when the nitrogen atom of the group is not directly bonded, E is -O- group, -S- group, -SO- group, -SO ₂ -
Group, -NR ₃ -group, -N (COR ₄ )-group, -CO- group, -NR ₃ -C
O-group, -CO-NR ₃ -group, -SO ₂ -NR ₃ -group, alkylsulfonylimino group or arylsulfonylimino group (in the formula,
₃ and R ₄ are as defined above), or C
_It may represent a _4-7 cycloalkylene group, which may be 4-membered or 5-membered.
In a 6-membered cycloalkylene ring, one ring member may represent a nitrogen atom, and in a 6-membered or 7-membered cycloalkylene ring, one or two ring members may each represent a nitrogen atom. Further, the methylene group adjacent to the nitrogen atom may be substituted by a carbonyl group, and at the same time, the bond to the carbon atom of the adjacent group may be carried out via any nitrogen atom present.

F is a bond, a straight-chain or branched C _1-6 alkylene group, a straight-chain or branched alkenylene group or alkynylene group having 2 to 6 carbon atoms, respectively (wherein the double bond or triple bond is the group E). Does not have to be directly adjacent to the hetero atom or triple bond of, and the above alkylene group, alkenylene group and alkynylene group are each an aryl group, -COO.
R ₆ group, -CON (R ₃ ) ₂ or -CO-N (R ₃ ) -alkyl group (in the formula,
R ₃ and R ₆ are optionally substituted by the above, and are also an alkyl part of a —CO—N (R ₃ ) -alkyl group, which contains 1 to 6 carbon atoms. But it may be)
May be further substituted by groups R ₇ and R ₈ , R
₇ and R ₈ (which may be the same or different) are each a hydrogen atom, an aryl group or —COO.
A R ₆ group, where R ₆ is as defined above, each having 4 to 6 carbon atoms in the cycloalkylene moiety, a cycloalkylene group, an alkylene-cycloalkylene group or a cycloalkylene. -Alkylene group (CH group arranged in the ring is substituted by a nitrogen atom, and the bond to the adjacent group E may be bonded via a nitrogen atom, and the bond may be bonded via a carbon atom of the group E. When D is a bond, E is an oxygen atom, and F is an alkyl group, A cannot be an amino group or an acylamino group directly bonded to the phenyl ring,
At the same time, when X is a sulfur atom and Y is a nitrogen atom, the group ABC cannot be a 4-acetamino-piperazino group), and

G represents a carbonyl group which is not bound to the heteroatom of the group E, which is a hydroxy group; an arylalkenyloxy group having 3 to 4 carbon atoms in the alkenyl moiety; a C _1-8 alkoxy group. (The C _1-5 alkoxy group may be substituted with an aryl group, or 1 to
The alkoxy group having 3 carbon atoms may be substituted at the 1-, 2- or 3-position by a heteroaryl group or a cycloalkyl group having 4-8 carbon atoms,
Or pyrrolidin-2-one-1- at the 2- or 3-position
Yl group, morpholino group, thiomorpholino group or 1-
Oxide-thiomorpholino group may be substituted); C _4-8 cycloalkoxy group optionally substituted with 1 to 3 alkyl groups; benzocycloalkoxy group, benzocycloalkyl-alkoxy group ,
A bicycloalkoxy group or a bicycloalkylalkoxy group (having 4 to 8 carbon atoms in the cycloalkyl moiety and 6 to 8 carbon atoms in the bicycloalkyl moiety, and optionally 1 to 3 carbon atoms) Optionally substituted by a methyl group); total 2 to 2 in the alkanoyl moiety
Alkanoyloxymethoxy groups having 7 carbon atoms; Cycloalkanoyloxy-methoxy groups having a total of 4 to 8 carbon atoms in the cycloalkanoyl moiety; Alkoxycarbonyloxy having 1 to 6 carbon atoms in the alkyl moiety Methoxy group; or cycloalkoxycarbonyloxymethoxy group having 3 to 7 carbon atoms in cycloalkyl moiety; aroyloxymethoxy group, aralkanoyloxymethoxy group, aryloxycarbonyloxymethoxy group or aralkoxycarbonyloxy group Methoxy group (in each case the methoxy moiety is
C _1-6 alkyl group, C _3-7 cycloalkyl group, or optionally substituted with an aralkyl group or an aryl group), or G is a sulfo group, a phosphono group, an O-alkylphospho group. Group or tetrazol-5-yl group,

Unless otherwise specified, each of the above alkyl, alkylene or alkoxy moieties is 1 to 3 respectively.
Carbon atoms may be included, and the term "aryl group" optionally includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; or an alkyl group, a trifluoromethyl group, a nitro group, an amino group, an alkylamino group. ,
Dialkylamino group, alkanoylamino group, alkylsulfonylamino group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group, hydroxy group, alkoxy group, aralkoxy group, carboxy group, alkoxycarbonyl group, aminocarbonyl group,
A phenyl group which may be mono-, di- or tri-substituted by an alkylaminocarbonyl group, a dialkylaminocarbonyl group, an alkylsulfenyl group, an alkylsulfinyl group or an alkylsulfonyl group (these substituents may be the same. , Or may be different), or a naphthyl group, and the term "heteroaryl group" refers to a 5-membered heteroaromatic ring (which is an imino group; an oxygen atom or a sulfur atom; 1 to 2 nitrogens). An atom and an oxygen atom or a sulfur atom; or an imino group and 1 to 3 nitrogen atoms), or a 6-membered heteroaromatic ring (which includes 1, 2 or 3 nitrogen atoms), The above ring may be condensed with a phenyl ring, and the above ring may further include a fluorine atom, a chlorine atom or a bromine atom; an alkyl group or an alkoxy group. , Hydroxy group, an amino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a trifluoromethyl group;
_{Alternatively,} it may be mono- or di-substituted by a C _1-4 alkylamino group.

Preferred compounds of the general formula I are those in which R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; an alkoxycarbonylamino group having 1 to 4 carbon atoms in the alkoxy part or an N-alkoxycarbonyl-alkyl group. Amino group; represents an alkyl group, a hydroxy group, an alkoxy group, a phenylalkoxy group, an amino group, an alkylamino group, a dialkylamino group, a pyrrolidino group, a piperidino group, an alkylcarbonylamino group or an alkylsulfonylamino group, unless otherwise specified. , Each alkyl moiety and alkoxy moiety may contain 1 to 3 carbon atoms, and the alkyl moiety of the alkylamino group and dialkylamino group is a carboxy group or an alkoxy moiety having 1 to 3 carbon atoms in the alkyl moiety. Replaced by a carbonyl group Even if good, X represents an oxygen atom, a sulfur atom or a nitrogen atom, or -NR ₂ groups (where
R ₂ is a hydrogen atom; a linear or branched C _1-14 alkyl group; an alkenyl group or an alkynyl group having 3 or 4 carbon atoms, respectively (wherein the double bond or triple bond is directly adjacent to the nitrogen atom). C _1-5 alkyl group [This is a carboxy group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, a phenylalkylaminocarbonyl group, a pyrrolidinocarbonyl group, a carboxyalkylamino group] A carbonyl group, an alkoxycarbonylalkylaminocarbonyl group, a 2- or 4-imidazolyl group or a pyridyl group; a piperidinocarbonyl group (the 4-position methylene group is an oxygen atom or a sulfenyl group, a sulfinyl group, a sulfonyl group, an imino group, Alkylimino group or phenylalkyl Phenyl group (optionally chlorine atom or bromine atom; or amino group, hydroxy group, alkoxy group or alkyl group; or mono- or di-substituted by two phenyl groups) C _3-7 cycloalkyl group; pyridyl group;
Optionally with a fluorine atom, a chlorine atom or a bromine atom or an alkyl group, an alkoxy group, an alkylsulfenyl group, an alkylsulfinyl group or an alkylsulfonyl group (these substituents may be the same or different) Represents a phenyl group which may be mono- or di-substituted, or R ₂ represents a C _2-4 alkyl group (which is a hydroxy group, an alkoxy group, an alkylsulfenyl group, an alkylsulfinyl group at the 2-position, 3-position or 4-position) Group, an alkylsulfonyl group, a 1-imidazolyl group, a pyrrolidino group or a piperidino group, and the methylene group at the 4-position is an oxygen atom, or a sulfenyl group, a sulfinyl group, a sulfonyl group, an imino group, an alkylimino group or a phenyl group. Optionally substituted by an alkylimino group ), Or R ₂ is in the second position, 3
Represents a C _2-6 alkyl group substituted by an amino group, an alkylamino group or a dialkylamino group at the 4-position, 5-position or 6-position) Unless otherwise specified, the alkyl moiety and the alkoxy moiety are each 1 ~ 3 carbon atoms may be included,

Y is a NO group, a nitrogen atom or, if necessary, C
_1-3 represents a methine group which may be substituted with an alkyl group, wherein Z ₁ , Z ₂ , Z ₃ and Z ₄ (which may be the same or different) are a methine group and a carbon atom. Represents an atom, an imino group or a nitrogen atom, at least one of the groups Z _{1 to} Z ₄ must contain a carbon atom, and one or two methine groups adjacent to the nitrogen atom are substituted with a carbonyl group. Alternatively, Z ₅ and Z ₆ each represent a carbon atom, or one of the groups Z ₅ or Z ₆ represents a nitrogen atom and the other group of the groups Z ₅ or Z ₆ represents a carbon atom and A is Cyano group; amino group; straight or branched C _1-4
Aminoalkyl group; represents an amidino group, a guanidino group or a guanidinoalkyl group, and in the above amino group, aminoalkyl group, amidino group, guanidino group or guanidinoalkyl group, one of the nitrogen atoms thereof has a hydrogen atom as C _{1- Four}
Alkyl group; C _2-5 (alkoxycarbonyl) group; phenylalkoxycarbonyl group, phenyloxycarbonyloxy group or benzoyl group; or alkanoyloxymethoxycarbonyl group (the alkanoyl part of which may contain a total of 2 to 4 carbon atoms) ); Or phosphono group, dialkylphosphoryl group or O-alkyl-
A may also be substituted by a phosphono group, or when B represents a cyclic imine, A is also a hydrogen atom or C
_1-3 alkyl groups (each of which is attached to an imino nitrogen) may be represented,

B is a phenylene group (which is a fluorine atom, a chlorine atom or a bromine atom; an alkyl group, a hydroxy group,
Monosubstituted or disubstituted with an alkoxy group, an alkylsulfenyl group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a trifluoromethyl group. And these substituents may be the same,
May be different, and the alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms), or B is a pyridinylene group or a cycloalkylene group having 3 to 6 carbon atoms; piperidinylene A group or a piperazinylene group (which may also be bonded via a nitrogen atom to a carbon atom of an adjacent group), an indaneylene group or a 1,2,3,4-tetrahydronaphthylene group (the saturated ring of which is a group A). And its aromatic ring is bound to a group C or a fused 5-membered heterocyclic group),

C is a bond, methylene group, ethylene group, phenylene group, O-methylene group, S-methylene group, SO-methylene group, SO ₂ -methylene group or N- (alkyl).
A methylene group (each of which is attached to the group B by a heteroatom), or methylene-N (alkyl)-
Group, each alkyl moiety may contain from 1 to 3 carbon atoms, D represents a bond or a methylene group or an ethylene group, E is a C _1-5 alkylene group, 3 to 5 carbon atoms each. Represents an alkenylene group or an alkynylene group having a double bond or triple bond of -Z ₁ -Z ₂ -Z _3-
Cannot be bonded directly to the nitrogen atom of the Z ₄ -group, or E is -Z
₁ -Z ₂ -Z ₃ -Z ₄ - if not coupled directly to the nitrogen atom of the group, it -O- group, -S- group, -SO- group, -S
O ₂ - group, -NH- group, -N (alkyl) - group, -N
(COalkyl)-group, -CO- group, -NH-CO-
Group, -N (alkyl) -CO- group, -CO-NH- group,
-CO-N (alkyl) - group, -SO ₂ -NH- group, -
It may represent a SO ₂ —N (alkyl) -group or an alkylsulfonylimino group (each alkyl part may contain 1 to 3 carbon atoms), a cyclohexylene group, a piperidinylene group or a piperazinylene group, Further, the methylene group adjacent to the nitrogen atom may be substituted with a carbonyl group, and at the same time, the bonding to the carbon atom of the adjacent group may be performed via the nitrogen atom.

F is a bond; C _1-4 alkylene group [which is a phenyl group, a carboxy group, an alkoxycarbonyl group, a phenylalkoxycarbonyl group or an alkylaminocarbonyl group (wherein the alkylaminocarbonyl group is an alkyl moiety (1-5 Phenyl group, hydroxyphenyl group, methoxyphenyl group, benzyloxyphenyl group, carboxy group, alkoxycarbonyl group or phenylalkoxycarbonyl group, or another carboxy group, alkoxycarbonyl group Or may be substituted with a phenylalkoxycarbonyl group)]; cyclohexylene group having 1 to 3 carbon atoms in the alkyl moiety, alkylene moiety and alkoxy moiety, respectively, cyclohexyl Down - alkylene group or alkylene - cyclohexylene group; piperidinylene group or pyrrolidinylene group (adjacent group E via these also nitrogen atom
A may be bonded to the group A through a carbon atom of the group E, and when D represents a bond, E represents an oxygen atom, and F is an alkyl group. Represents an amino group or an acylamino group directly bonded to the phenyl ring), and

G represents a carbonyl group which is not bound to the heteroatom of the group E, which is a hydroxy group; a cinnamyloxy group; a C _1-6 alkoxy group (wherein the C _1-5 alkoxy group is replaced by a phenyl group). Or a C _1-3 alkoxy group may be substituted at the 1, 2 or 3 position by a naphthyl group, a C _5-6 cycloalkyl group, a pyridyl group, or at the 2 or 3 position. Pyrrolidin-2-one-
1-yl group may be substituted); C _5-8 cycloalkoxy group; indanyloxy group or 1, 2, 3,
4-tetrahydronaphthyloxy group; bicycloheptyloxy group or bicycloheptylmethoxy group (the bicycloheptyl group may be substituted by 1 to 3 methyl groups); a total of 2 to 5 carbon atoms in the alkanoyl moiety An alkanoyloxymethoxy group having: an alkoxycarbonyloxymethoxy group having 1 to 2 carbon atoms in the alkyl moiety; or a cycloalkoxycarbonyloxymethoxy group having 5 or 6 carbon atoms in the cycloalkyl moiety (respectively The methoxy moiety of which may be substituted by an alkyl group) or G is an O-alkylphosphono group having 1 to 3 carbon atoms or a sulfo group, a phosphono group or tetrazole-5. A compound, its tautomer, which represents an -yl group, Stereoisomers including mixtures, and their salts, in particular inorganic or organic acids or bases and these physiologically acceptable salt thereof.

However, especially preferred compounds of the above general formula I are those in which R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; Group; alkoxycarbonylamino group or N-alkoxycarbonyl-methylamino group each having 1 to 4 carbon atoms in the alkoxy moiety; methyl group, hydroxy group, amino group, methylamino group, dimethylamino group, N
-Carboxymethyl-amino group, N-carboxymethyl-methylamino group, N-methoxycarbonylmethyl-methylamino group, acetylamino group, piperidino group, or methylsulfonylamino group,

X represents an oxygen atom, a sulfur atom or a nitrogen atom or a --NR ₂ group, wherein R ₂ is a hydrogen atom; a straight chain or branched C _1-14 alkyl group; an allyl group or a propargyl group; Group, methoxycarbonyl group, ethoxycarbonyl group, aminocarbonyl group, methylaminocarbonyl group, dimethylaminocarbonyl group, benzylaminocarbonyl group, phenylethylaminocarbonyl group, carboxymethylaminocarbonyl group, methoxycarbonylmethylaminocarbonyl group, or pyridyl Radical; or C substituted by a piperidinocarbonyl group
_1-3 alkyl group, the 4-position methylene group may be substituted with an oxygen atom, a sulfenyl group, a sulfinyl group, a sulfonyl group, an imino group or a benzylimino group, or R ₂ is C _{1- 4} Alkyl groups (which are optionally substituted by bromine or chlorine atoms or by phenyl groups which may be mono- or disubstituted by amino, hydroxy, methoxy or methyl groups, or which are Substituted with a phenyl group), or R ₂ is a C _3-6 cycloalkyl group; a pyridyl group; a chlorine atom or a methyl group if necessary,
Represents a phenyl group which may be mono- or di-substituted by a methoxy group, a methylsulfenyl group, a methylsulfinyl group or a methylsulfonyl group (these substituents may be the same or different) ,
Or R ₂ is a C _2-3 alkyl group (which is substituted at the 2- or 3-position by a hydroxy group, a methoxy group, a methylsulfenyl group, a methylsulfinyl group, a methylsulfonyl group, an imidazolyl group, a pyrrolidino group or a piperidino group. And the 4-position methylene group may be substituted with an oxygen atom, a sulfenyl group, a sulfinyl group, a sulfonyl group, an imino group or a benzylimino group), or R ₂ is the 2-position, 3-position, 4-position Represents a C _2-6 alkyl group substituted with an amino group at the 5th or 6th position)

Y represents an NO group, a nitrogen atom or a methine group which may be optionally methyl-substituted, Z ₁ ,
Z ₂ , Z ₃ and Z ₄ (which may be the same or different) represent a methine group, a carbon atom, an imino group or a nitrogen atom, and at least one of the groups Z _{1 to} Z ₄ Must contain a carbon atom, and one or two methine groups adjacent to the nitrogen atom may be substituted by a carbonyl group, Z ₅ and Z ₆ each represent a carbon atom, or the group Z ₅ Or one of Z ₆ represents a nitrogen atom,
And another group of groups Z ₅ or Z ₆ represents a carbon atom,
Represents an amino group; a linear or branched C _1-3 aminoalkyl group; an amidino group, a guanidino group or a guanidinomethyl group, and the above amino group, aminoalkyl group, amidino group,
In a guanidino group or a guanidinomethyl group, one of its nitrogen atoms is a C _1-4 alkyl group; an alkoxycarbonyl group having a total of 2 to 5 carbon atoms; or a benzyloxycarbonyl group, acetyloxymethoxycarbonyl group Group, may be substituted with a dimethylphosphoryl group or a diethylphosphoryl group,

B is a phenylene group (which may be substituted with a fluorine atom, a chlorine atom or a bromine atom; or a methyl group, a hydroxy group or a methoxy group);
Pyridinylene group or C _3-6 cycloalkylene group; indanylene group or 1,2,3,4-tetrahydronaphthylene group (in each case, its saturated ring is bound to group A and its aromatic ring is group C or A fused 5-membered heterocyclic group), or B represents a piperidinylene group or a piperazinylene group (which may also be bonded via a nitrogen atom to a carbon atom of an adjacent group) and C is A bond, a phenylene group or an O-methylene group, D represents a bond or a methylene group, E is a C _3-5 alkylene group, C
_3-5 represents an alkenylene group, in which the double bond is Z ₁ -Z ₂
E may not be directly bonded to the nitrogen atom of the -Z ₃ -Z ₄ group, or if E is not directly bonded to the nitrogen atom of the Z ₁ -Z ₂ -Z ₃ -Z ₄ group, then E Is an -O- group, an -S- group,
-SO- group, -SO ₂ - group, -NH- group, -N (methyl) - group, -N (acetyl) - group, -N (SO ₂ CH ₃₎ - group, -
CO- group, -NH-CO- group, -N (CH ₃₎ -CO-
Group, -CO-NH- _{group, -CO-N (CH 3)} - group, -S
It may represent an O ₂ —NH— group or a —SO ₂ —N (CH ₃ ) — group, or E represents a piperidinylene group, a piperazinylene group or an oxo-piperazinylene group, these nitrogen atoms also being carbon atoms of adjacent groups. May be attached to an atom,

F is bonded; C _1-4 alkylene group [This is a phenyl group, a carboxy group, a methoxycarbonyl group, a benzyloxycarbonyl group, a phenylethylaminocarbonyl group, a (methoxyphenyl) ethylaminocarbonyl group or an alkylaminocarbonyl group. (Wherein the alkylaminocarbonyl group is substituted in the alkyl part (which may contain 1 to 4 carbon atoms) by a phenyl group, a hydroxyphenyl group, a methoxyphenyl group, a carboxy group or a benzyloxycarbonyl group. Or may be further substituted by another carboxy group or a benzyloxycarbonyl group)]; a piperidinylene group or a pyrrolidinylene group (each of which is bound to the nitrogen atom of the group E). Done through Provided that it may be bonded to the adjacent group E via a nitrogen atom), or a cyclohexylene group or a cyclohexylene-methylene group, (D represents a bond, E represents an oxygen atom, and When F represents an alkyl group, A must not be an amino group or an acylamino group directly bonded to the phenyl ring)

G represents a carbonyl group which is not bound to the heteroatom of the group E, which is a hydroxy group; a C _1-6 alkoxy group (which may be substituted in the 1 to 5 positions by a phenyl group). , Or may be substituted at the 1-position or 2-position with a cyclohexyl group, a naphthyl group or a pyridyl group, or at the 2-position pyrrolidin-2-one-1
-May be substituted by an yl group); cinnamyloxy group; C _6-8 cycloalkoxy group; indanyloxy group, norbornyloxy group or norbornylmethyloxy group; total 2 to alkanoyl moieties An alkanoyloxymethoxy group having 5 carbon atoms; an alkoxycarbonyloxymethoxy group having 1 to 3 carbon atoms in the alkoxy moiety; or a cyclohexyloxy-carbonyloxymethoxy group, the methoxy moiety of which is methyl Optionally substituted by a group,
Or G may represent a sulfo group, a phosphono group, an O-methyl-phosphono group or a tetrazol-5-yl group, a compound, in particular

R ₁ is hydrogen atom or methyl group, methoxy group, methylamino group, dimethylamino group, N-butyloxycarbonyl-methylamino group, N-isobutyloxycarbonyl-methylamino group, N-carboxymethyl-amino group , N-carboxymethyl-methylamino group,
N-methoxycarbonylmethyl-amino group or N-
A methoxycarbonylmethyl-methylamino group, X
Is an oxygen atom or a nitrogen atom or a -NR ₂ group,
[Wherein R ₂ is a hydrogen atom; a linear or branched C _1-14 alkyl group; a C _1-3 alkyl group (which is substituted with a carboxy group or a methoxycarbonyl group); a C _1-4 alkyl group (This is optionally substituted by a phenyl group which may be mono- or di-substituted by a bromine atom, an amino group or a methoxy group, or by two phenyl groups or a pyridyl group); Or substituted at position 3 by an amino group or a piperidino group
A C _2-3 alkyl group (the methylene group at the 4-position thereof is substituted with an imino group, a benzylimino group, a sulfenyl group, a sulfinyl group or a sulfonyl group)]

Y represents a NO group, a nitrogen atom or a methine group, and Z ₁ , Z ₂ , Z ₃ and Z ₄ (which may be the same or different) are methine groups and carbon atoms. , An imino group or a nitrogen atom, at least two of the groups Z _{1 to} Z ₄ must contain carbon atoms, and one or two methine groups adjacent to the nitrogen atom are each substituted by a carbonyl group. Alternatively, Z ₅ and Z ₆ each represent a carbon atom, or one of the groups Z ₅ or Z ₆ represents a nitrogen atom and the other group of the groups Z ₅ or Z ₆ represents a carbon atom and A is Represents an aminomethyl group or an amidino group, one of the nitrogen atoms of which a hydrogen atom may be replaced by a methoxycarbonyl group, B represents a phenylene group, C represents a bond or an O-methylene group, and D represents represents a bond, E is C _3-4 alkylene It represents a group, or, E is -
When not directly bonded to the nitrogen atom of the Z ₁ -Z ₂ -Z ₃ -Z ₄ -group, E is -O- group, -NH-CO- group or -C.
May represent an O—NH— group, F represents a bond or a C _1-3 alkylene group, and G represents a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, or a cyclohexyloxy group, A compound, its tautomer,
Stereoisomers including their mixtures and salts thereof, especially inorganic or organic acids or bases and their physiologically acceptable salts.

According to the invention, the novel compounds of the general formula I can be obtained, for example, by the methods known per se below. a) To prepare compounds of general formula I in which G represents a carboxyl group, the general formula:

[0027]

[Chemical 19]

Where A to F, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above, and G ′ (which is attached to a carbon atom) is hydrolyzed. A compound capable of being converted into a carboxyl group by decomposition, treatment with an acid, thermal decomposition or hydrogenolysis). For example, a functional derivative of a carboxyl group, such as an unsubstituted or substituted amide, ester, thioester, trimethylsilyl ester, orthoester, iminoester, amidine or acid anhydride, or a nitrile group can be converted to a carboxyl group by hydrolysis. Esters with tertiary alcohols, such as tert.butyl ester, can be converted to carboxyl groups by treatment with acid or thermal decomposition, and esters with aralkanol, such as benzyl ester, can be converted to carboxyl groups by hydrogenolysis, and Bis (alkoxycarbonyl) methyl groups can be converted to bis (hydroxycarbonyl) methyl groups by hydrolysis or treatment with acid, which is subsequently decarboxylated.
Hydrolysis may be carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, water, methanol, water. / In a suitable solvent such as methanol, ethanol, water / ethanol, water / isopropanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 ° C and 120 ° C, for example ambient temperature to a boiling temperature of the reaction mixture. To be done.
When treated with an organic acid such as trichloroacetic acid or trifluoroacetic acid, the alcoholic hydroxy groups present can be converted simultaneously to the corresponding acyloxy groups such as trifluoroacetoxy groups.

When G'in the compounds of the general formula II represents a cyano group or an aminocarbonyl group, these groups can also be substituted in the presence of an acid such as sulfuric acid, which at the same time can be suitably used as a solvent, with It may be converted to a carboxyl group with a nitrite, for example sodium nitrite, at a temperature of ~ 50 ° C. When G'in the compound of formula II represents, for example, a tert. Butyloxycarbonyl group, the tert. Butyl group may also be optionally substituted in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, Preferably a temperature of -10 ℃ ~ 120 ℃, for example 0 ~ 60
It can be cleaved by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid at a temperature of ° C, or if necessary methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane. In an inert solvent such as, preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. It can be cleaved by pyrolysis at a temperature of 100 ° C. G'in the compound of formula II is
For example, when representing a benzyloxycarbonyl group, the benzyl group may also be in the presence of a hydrogenation catalyst such as palladium / charcoal in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide. Cleavage by hydrogenolysis under hydrogen pressure of 1-10 bar, preferably at a temperature of 0-50 ° C., for example ambient temperature. During the hydrogenolysis, other groups can also be reduced simultaneously, for example nitro groups can be reduced to amino groups and benzyloxy groups can be reduced to hydroxy groups.

B) To prepare the benzimidazoles of the general formula I, the general formula:

[0031]

[Chemical 20]

(Wherein A to G, R ₁ , R ₂ and Z _{1 to} Z
₄ is as defined above, and Y ₁ represents an amino group). The cyclization may be carried out with a solvent or mixture of solvents such as methanol, ethanol,
Excess acylating agent used in isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or to prepare compounds of general formula III In a corresponding acid or a corresponding nitrile, acid anhydride, acid halide, ester or amide, for example at a temperature of 0 to 250 ° C., preferably at the boiling temperature of the reaction mixture, optionally a condensing agent such as ,
Phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride, or potassium ethoxide or potassium tert.
It is conveniently carried out in the presence of a base such as butoxide. However, the cyclization may also be carried out without the use of solvents and / or condensing agents.

However, by acylating the corresponding diamino compound or by the corresponding o-nitro-
It is particularly advantageous to carry out the reaction by preparing a compound of general formula III in the reaction mixture by reducing the acylamino compound. If the reduction of the nitro group is interrupted at the hydroxyamine step, subsequent cyclization yields the N-oxide of general formula I. The N-oxide thus obtained may subsequently be converted to the corresponding compound of general formula I by reduction. Subsequent reduction of the resulting N-oxide of formula I is accomplished with a solvent such as water, water / ethanol, methanol,
Hydrogen, in the presence of hydrogenation catalysts such as Raney nickel, platinum or palladium / charcoal in glacial acetic acid, ethyl acetate or dimethylformamide, and in the presence of acids such as acetic acid, hydrochloric acid or sulfuric acid, of iron, tin or zinc. With metals such as, and with salts such as iron (II) sulfate, tin (II) chloride or sodium dithionite, and trivalent phosphorus derivatives such as triphenylphosphine, triethylphosphite or phosphorus trichloride. It is preferably carried out with or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50 ° C., preferably at ambient temperature.

C) In order to prepare compounds of general formula I in which A represents an amidino group optionally substituted by alkyl groups, a general formula optionally produced in the reaction mixture:

[0035]

[Chemical 21]

(Wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above, and X ₁ is an alkoxy group or an aralkoxy group, for example, a methoxy group,
An ethoxy group, an n-propoxy group, an isopropoxy group or a benzyloxy group or an alkylthio group or an aralkylthio group, for example, a methylthio group, an ethylthio group, an n-propylthio group or a benzylthio group or an amino group is represented by the general formula: R _a —NH ₂ (V) (In the formula, R _a represents a hydrogen atom or a C _1-4 alkyl group)
The reaction with the amine or its acid addition salt. The reaction is carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at a temperature of 0 to 150 ° C, preferably 20 ° C.
Suitably carried out at a temperature of .about.120.degree. C. with the corresponding free amine or the corresponding acid addition salt, eg ammonium carbonate or ammonium acetate. The compound of general formula IV is
For example, the corresponding nitrile in the presence of an acid such as hydrochloric acid,
Or by reacting the corresponding amide with methylene chloride, tetrahydrofuran, by reacting with a suitable alcohol, for example methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of the corresponding alkoxide such as sodium methoxide or sodium ethoxide. Or by reacting with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as dioxane at a temperature of -10 to 50 ° C, preferably 0 to 20 ° C,
Or by reacting the corresponding nitrile with hydrogen sulphide in the presence of a base such as triethylamine, suitably in a solvent such as pyridine or dimethylformamide, followed by alkylation of the resulting thioamide with the corresponding alkyl or aralkyl halide. Obtainable.

D) To prepare compounds of the general formula I in which A represents an aminoalkyl group, the general formula:

[0038]

[Chemical formula 22]

Reducing compounds of the formula: BG, R ₁ , Z ₁ -Z ₆ , X and Y are as defined above and A ₁ represents a cyano group or cyanoalkyl. Method. The reduction may be carried out in a suitable solvent, for example methanol, methanol / water, methanol / ammonia, methanol /
Catalytically activated hydrogen in water / ammonia, methanol / hydrochloric acid, ethanol, ether, tetrahydrofuran, dioxane, dimethylformamide or glacial acetic acid, eg Raney nickel, platinum or palladium /
In the presence of hydrogen in the presence of charcoal, or metal hydrides,
For example, 0-100 in the presence of sodium borohydride, lithium borohydride or lithium aluminum hydride.
It is preferable to carry out at a temperature of ℃, preferably at a temperature of 20-80 ℃.

E) To prepare compounds of general formula I containing a sulfinyl or sulfonyl group which is not bound to a nitrogen atom, a compound of the general formula:

[0041]

[Chemical formula 23]

(Wherein A to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above, provided that the groups R ₁ ,
A compound of the formula B), C, E, G or X, provided that at least one of B, C, E, G or X contains a sulfenyl group or a sulfinyl group which is not bonded to a nitrogen atom. The oxidation may be carried out with a solvent or mixture of solvents, for example water, water /
Pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid /
It is preferably carried out in acetic anhydride, dilute sulfuric acid or trifluoroacetic acid at a temperature of -80 to 100 ° C, depending on the oxidizing agent used. To prepare the corresponding S-oxide compound of general formula I, the oxidation is carried out using 1 equivalent of oxidizing agent,
For example, in glacial acetic acid, trifluoroacetic acid or formic acid 0 to
Using hydrogen peroxide at 20 ° C or 0-60 ° C in acetone, and 0- 0 in glacial acetic acid or trifluoroacetic acid.
Using peracids such as formic acid at 50 ° C, m-chloroperbenzoic acid in methylene chloride or chloroform at -20 ° C to 60 ° C, and -15 ° C in aqueous methanol or ethanol. Using sodium metaperiodate at 25 ° C, optionally using bromine in glacial acetic acid or aqueous acetic acid in the presence of a weak base such as sodium acetate, and using N-bromo-succinimide in ethanol. And also in methanol at -80 ° C to -30 ° C tert.
Butyl-hypochlorite, and iodobenzodichloride in aqueous pyridine at 0-50 ° C, and nitric acid in glacial acetic acid at 0-20 ° C, and glacial acetic acid or The thioether-chlorine complex obtained is conveniently hydrolyzed with aqueous ethanol using chromic acid in acetone at 0 to 20 ° C and sulfuryl chloride in methylene chloride at -70 ° C. It

In order to prepare the corresponding S, S-dioxide compounds of the general formula I, the oxidation is carried out starting from the corresponding alkylsulfinyl compound with one or more equivalents of oxidizing agent or by the corresponding alkylsulfenyl compound. Starting from the compound, two or more equivalents of oxidizing agent are used, for example 20 to 10 in glacial acetic acid / acetic anhydride, trifluoroacetic acid or formic acid.
Using hydrogen peroxide at 0 ° C or in acetone at 0-60 ° C and in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at 0-60 ° C formic acid or m-.
Chromic acid or permanganese using peracids such as chloroperbenzoic acid and nitric acid in glacial acetic acid at 0-20 ° C and in glacial acetic acid, water / sulfuric acid or acetone at 0-20 ° C. Suitably done using potassium acidate.

F) A is substituted by an alkoxycarbonyl group having 2 to 5 carbon atoms in total or an arylmethoxycarbonyl group, an arylethoxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an aralkylcarbonyl group or an arylcarbonyl group. To prepare a compound of general formula I which represents an amino group, an aminoalkyl group, an amidino group, a guanidino group or a guanidinoalkyl group.

[0045]

[Chemical formula 24]

(Wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above, and A ₂ is an amino group, an aminoalkyl group, an amidino group, a guanidino group or A compound of guanidinoalkyl group is represented by the general formula: X ₂ —COR _b (IX) (wherein R _b is a C _1-4 alkoxy group, arylmethoxy group, arylethoxy group, aryloxy group, alkyl group, aralkyl) A group or an aryl group, and X ₂ represents a nucleophilic leaving group such as a halogen atom, for example, a chlorine atom or a bromine atom). The reaction is carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform or dimethylformamide,
Suitably in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution, or a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine (these are simultaneously used as solvent). Available) in the presence of
It is conveniently carried out at a temperature of -30 to 100 ° C, preferably -10 to 80 ° C.

G) G represents a carbonyl group which is not bound to the heteroatom of the group E, which is a cinnamyloxy group;
C _1-6 alkoxy group (C _1-5 alkoxy group may be substituted by phenyl group, or C _1-3 alkoxy group may be 1
Optionally substituted at the 2-, 3- or 3-position with a naphthyl group, a C _5-6 cycloalkyl group, a pyridyl group, or 2
Optionally substituted by a pyrrolidin-2-one-1-yl group at position 3 or 3); C _5-8 cycloalkoxy group; indanyloxy group, 1,2,3,4-tetrahydronaphthyloxy group, Bicycloheptyloxy group or bicycloheptylmethoxy group; alkanoyloxymethoxy group having a total of 2 to 5 carbon atoms in the alkanoyl moiety; alkoxycarbonyloxymethoxy group having 1 to 2 carbon atoms in the alkyl moiety; or cyclo Preparing a compound of general formula I which is substituted by a cycloalkoxycarbonyloxymethoxy group having 5 or 6 carbon atoms in the alkyl moiety, the methoxy moiety being in each case optionally substituted by an alkyl group For general formula:

[0048]

[Chemical 25]

Compounds of the general formula A to F, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above and G ″ represents a carboxy group or an alkoxycarbonyl group. _{wherein: X 3 -R c (XI)} ( wherein, X ₃ represents such a nucleophilic leaving group hydroxy group or a halogen atom, e.g., chlorine atom, bromine atom or iodine atom, and R _c is cinnamyl Oxy group; C _1-6
Alkyl group (C _1-5 alkyl group may be substituted by phenyl group, or C _1-3 alkyl group may be naphthyl group, C _5-6 cycloalkyl group, pyridyl group at 1-position, 2-position or 3-position) Or a pyrrolidin-2-one-1-yl group at the 2- or 3-position); C _5-8 cycloalkyl group; indanyl group, 1, 2, 3 , 4-tetrahydronaphthyl group, bicycloheptyl group or bicycloheptylmethyl group; alkanoyloxymethyl group having a total of 2 to 5 carbon atoms in the alkanoyl moiety; alkoxycarbonyl having 1 to 2 carbon atoms in the alkyl moiety An oxymethyl group; or a cycloalkoxycarbonyloxymethyl group having 5 or 6 carbon atoms in the cycloalkyl moiety, each of which How chill moiety is reacted with an alcohol of an alkyl may be substituted by a group).

The reaction is carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulfoxide, toluene, chlorobenzene, tetrahydrofuran, toluene / tetrahydrofuran or dioxane, optionally in the presence of an acid such as hydrochloric acid, or In the presence of a dehydrating agent, for example, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, titanium tetrachloride, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N '. -Dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-
Carbonyldiimidazole or N, N′-thionyldiimidazole or in the presence of triphenylphosphine / carbon tetrachloride or a base such as sodium carbonate, potassium carbonate, sodium hydroxide solution, triethylamine, N-ethyl-diisopropylamine, It is conveniently carried out in the presence of N-methyl-morpholine, pyridine or 4-dimethylamino-pyridine, suitably at a temperature of 0 to 150 ° C, preferably at a temperature of 0 to 50 ° C.

When X ₃ represents a nucleophilic leaving group, the reaction is carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide or dimethylformamide, if necessary, by promoting a reaction such as sodium iodide or potassium iodide. In the presence of an agent, preferably a base,
For example, in the presence of sodium carbonate, potassium carbonate or sodium hydroxide solution, or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent. Or optionally in the presence of silver carbonate or silver oxide at a temperature of -30 to 100 ° C, preferably -10 to 80
It is conveniently carried out at a temperature of ° C. When X ₃ represents a hydroxy group, its esterification is carried out in a solvent or a mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulfoxide, toluene, chloroform, tetrahydrofuran, toluene / tetrahydrofuran or dioxane, optionally with an acid such as hydrochloric acid. Or in the presence of a dehydrating agent, for example, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, titanium tetrachloride, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, pentoxide. Phosphorus, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-
In the presence of carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, a temperature of -30 to 100 ° C, preferably -10
Conveniently performed at a temperature of ~ 60 ° C.

H) To prepare compounds of general formula I in which A represents an amidino group attached to the nitrogen atom of a guanidinoalkyl group or a cyclic imino group, the general formula:

[0053]

[Chemical formula 26]

A compound of the formula: BG, R ₁ , Z ₁ -Z ₆ , X and Y is as defined above and A ₃ represents an aminoalkyl group, or a general formula:

[0055]

[Chemical 27]

(Wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above, provided that group B contains a cyclic imino group). A method of reacting a compound with S-alkyl-isothiourea. The reaction is carried out in a solvent such as dimethylformamide, preferably in the presence of a base such as sodium carbonate, at elevated temperature, for example 80-120.
It is conveniently carried out at a temperature of ° C.

I) to prepare compounds of general formula I in which A represents a guanidino group attached to the aromatic ring, the general formula:

[0058]

[Chemical 28]

(In the formula, B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined above, provided that B represents an aromatic ring or a heteroaromatic ring. And A
₄ represents an amino group) and the compound is reacted with cyanamide or an acid addition salt thereof. The reaction is conveniently carried out in a solvent such as dioxane, dioxane / water or tetrahydrofuran, preferably at a temperature of 60 to 120 ° C., for example the boiling temperature of the reaction mixture.

J) D represents a bond, and E is -NR ₃ -C
To prepare compounds of general formula I which represent an O-group, the general formula:

[0061]

[Chemical 29]

(Wherein A to C, R ₁ , R ₃ and Z ₁ to
Z ₆ , X and Y are as previously defined) and a compound of the general formula: X ₄ —CO—FG (XVI), where F and G are as previously defined, And X ₄ represents a hydroxy group or an alkoxy group or a nucleophilic leaving group such as a halogen atom, for example, a chlorine atom, a bromine atom or an iodine atom, or a methoxy group or an ethoxy group), or a reactive derivative thereof. Method. The reaction is carried out in a solvent such as methylene chloride,
Chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activator or dehydrating agent, such as ethyl chloroformate, thionyl chloride, phosphorus trichloride. , Phosphorus pentoxide,
N, N'-dicyclohexylcarbodiimide, N, N '
-Dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of an inorganic base such as sodium carbonate or a tertiary In the presence of an organic base such as triethylamine, pyridine or 4-dimethylamino-pyridine, which can be used simultaneously as a solvent, a temperature of -25 to 150 ° C, preferably -1
It is suitably carried out at a temperature between 0 ° C. and the boiling temperature of the solvent used. However, the acylation is preferably carried out as described above with the corresponding acid halide or anhydride, but may also be carried out without solvent.

K) To prepare compounds of the general formula I in which A represents an amino group or an aminoalkyl group, the general formula:

[0064]

[Chemical 30]

(Wherein R ₁ , BG, X, Y and Z ₁
Z ₆ is as defined above and A ₅ is H ₂ N
A compound having a —CO—T group (wherein T represents a bond or a C _1-4 alkylene group) is represented by the general formula:

[0066]

[Chemical 31]

A method in which R ₉ represents an acyl group of an organic carboxylic acid, for example, an acetoxy group or a trifluoroacetoxy group, and is reacted with a phenyliodo (III) compound. The reaction is preferably carried out in an aqueous solvent such as water or water / acetonitrile at a temperature of 0 to 50 ° C, preferably at ambient temperature.

L) A is an aminoalkyl group, the amino group of which is not bound to a quaternary carbon atom, or an amino group which is bound to the CH or CH ₂ group of groups B or C. To prepare compounds of general formula I
General formula:

[0069]

[Chemical 32]

(Wherein R ₁ , BG, X, Y and Z ₁
Z ₆ is as defined above, and A ₆ represents a hydroxyimino group or a hydroxyiminoalkyl group having 1 to 4 carbon atoms). The reduction is catalytically activated by adding an acid such as hydrochloric acid in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, if necessary. Hydrogen in the presence of hydrogen, for example Raney nickel, platinum or palladium / charcoal, at a temperature of 0-100 ° C, preferably 20-80 ° C.
Is preferably carried out at the temperature of.

M) of the general formula I in which A represents an amino group, an aminoalkyl group, an amidino group, a guanidino group or a guanidinoalkyl group, each of which is substituted by a dialkylphosphoryl group having 1 to 3 carbon atoms in the alkyl moiety. To prepare the compound, the general formula:

[0072]

[Chemical 33]

(Wherein R ₁ , B to G, X, Y and Z ₁ to
Z ₆ is as defined above, and A ₇ has 1 to 3 carbon atoms in the amino group, straight chain or branched C _1-4 aminoalkyl group, amidino group, guanidino group or alkyl moiety. Having a compound of the formula: X ₅ —PO (OR ₁₀ ) ₂ (XXI) (wherein R ₁₀ represents a C _1-3 alkyl group, and X ₅ is a nucleophilic elimination group). Group, eg, a cyano group or a chlorine atom or a bromine atom). The reaction is conveniently carried out in a solvent such as dimethylformamide at a temperature of 0 to 100 ° C, preferably 15 to 50 ° C.

N) a general formula I in which E represents a —CO—NR ₃ — group
To prepare compounds of the general formula:

[0075]

[Chemical 34]

A compound of the formula: where A to D, X, Y and Z _{1 to} Z ₆ are as defined above is represented by the general formula: HNR ₃ -FG (XXIII) (wherein F , G and R ₃ are as defined above). The reaction is carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activator or dehydrating agent, for example: Ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole , 2- (1H-benzotriazol-1-yl)
-1,1,3,3-tetramethyluronium-tetrafluoroborate, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, optionally in the presence of An inorganic base such as sodium carbonate or a tertiary organic base,
For example, triethylamine, N-methyl-morpholine,
In the presence of pyridine or 4-dimethylaminopyridine (which can be simultaneously used as a solvent), -25 to 15
Suitably it is carried out at a temperature of 0 ° C., preferably −10 ° C. to the boiling temperature of the solvent used.

If, according to the invention, a compound of the general formula I in which R ₁ represents one of the abovementioned amino or aminoalkyl groups is obtained, this is carried out by alkylation, which is the corresponding alkylamino or dialkylamino compound of the general formula I. Can be converted to. Subsequent alkylation is carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, dimethylsulfoxide, toluene, chlorobenzene, tetrahydrofuran, toluene / tetrahydrofuran or dioxane, optionally with a base such as sodium carbonate, potassium carbonate, water. Sodium oxide solution,
It is conveniently carried out in the presence of potassium tert. Butoxide or N-ethyl-diisopropylamine at a temperature of 0 to 150 ° C, preferably at a temperature of 0 to 50 ° C.

In the above reaction, the reactive group present,
For example, hydroxy, carboxy, phosphono, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups, which are cleaved again after the reaction. For example, the protecting group for hydroxy group may be trimethylsilyl group, acetyl group, benzoyl group, tert.butyl group, trityl group, benzyl group or tetrahydropyranyl group, and the protecting group for carboxyl group may be trimethylsilyl group, methyl group, It may be an ethyl group, a tert.butyl group, a benzyl group or a tetrahydropyranyl group, a phosphono group may be a trimethylsilyl group, a methyl group, an ethyl group or a benzyl group, and an amino group, an alkylamino group. The protecting group for the group or imino group is acetyl group, trifluoroacetyl group, benzoyl group, ethoxycarbonyl group, tert.butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, methoxybenzyl group or 2,4-dimethoxybenzyl group. And the lid on the amino group Le groups are also contemplated.

Any subsequent cleavage of the protecting group can be accomplished, for example, by
In an aqueous solvent such as water, isopropanol / water, tetrahydrofuran / water or dioxane / water in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid or sulfuric acid, or an alkali metal base such as hydroxylation. It may be carried out by hydrolysis in the presence of lithium, sodium hydroxide or potassium hydroxide, or by ether cleavage, for example in the presence of iodotrimethylsilane at a temperature of 0 to 100 ° C, preferably at a temperature of 10 to 50 ° C. . However, a benzyl group, a methoxybenzyl group or a benzyloxy-carbonyl group may, for example, be hydrogenated in the presence of a solvent such as palladium / charcoal in the presence of a catalyst such as palladium on charcoal.
In methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with addition of an acid such as hydrochloric acid, at a temperature of 0 to 50 ° C., preferably at ambient temperature, at a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar. Originally, it can be cleaved by hydrogenolysis. The methoxybenzyl group is also cleaved in a solvent such as methylene chloride, acetonitrile or acetonitrile / water in the presence of an oxidizing agent such as cerium (IV) -ammonium nitrate at a temperature of 0 to 50 ° C., preferably at ambient temperature. obtain. However, the 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisole.

Cleavage of only one alkyl group from an O, O'-dialkylphosphono group is carried out using sodium iodide in a solvent such as acetone, ethylmethylketone, acetonitrile or dimethylformamide at 40-150 ° C. It is preferred that it be carried out at a temperature, preferably between 60 and 100 ° C. Cleavage of both alkyl groups from an O, O'-dialkylphosphono group is carried out, for example, using iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane / sodium iodide in a solvent such as methylene chloride, chloroform or acetonitrile. It is carried out at a temperature of from 0 ° C to the boiling temperature of the reaction mixture, preferably from 20 to 60 ° C. The tert. butyl group or tert. butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether. The phthalyl group is cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at a temperature of 20-50 ° C. It is preferable.

Furthermore, the compounds of general formula I obtained may be resolved into their enantiomers and / or diastereomers as described above. Thus, for example, cis / trans mixtures can be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom can be resolved into their enantiomers. Thus, for example,
The cis / trans mixture obtained can be separated into its cis and trans isomers by chromatography,
The compounds of general formula I which occur in racemic form are then prepared by methods known per se (Allinger NL and Eliel EL, "Topics in Stereochemistry", Volume 6, Wiley Intersci).
ence, 1971) and their optical enantiomers, and which have at least two asymmetric carbon atoms, can be prepared using known methods, for example by:
They can be separated into their diastereomers on the basis of their physicochemical differences by chromatography and / or fractional crystallization, which, if they occur in racemic form, are subsequently resolved into enantiomers as described above. obtain.

The resolution of the enantiomers can be achieved by column separation with a chiral phase or recrystallization with an optically active solvent, or an optically active substance which produces a racemate and a salt or derivative such as an ester or amide, especially an acid or active derivative thereof. It is preferably carried out by reaction with an alcohol and separation of the thus obtained diastereomeric salt mixture or derivative (for example separation based on their different solubilities), while the free enantiomer is separated by the action of a suitable agent. It can be liberated from pure diastereomeric salts or derivatives. Particularly common optically active acids include, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Optically active alcohols are, for example,
It may be (+) menthol or (-) menthol, and the optically active acyl group in the amide is, for example,
It may be (+) menthyloxycarbonyl or (−) menthyloxycarbonyl.

Furthermore, the compound of formula I obtained is a salt thereof,
It may be converted into its physiologically acceptable salts with inorganic or organic acids, especially for pharmaceutical use. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. In addition, the novel compounds of formula I thus obtained, if they contain a carboxyl group, are then optionally
Inorganic or organic bases and their addition salts, more particularly,
For pharmaceutical use, they may be converted into their physiologically acceptable addition salts. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The compounds used as starting materials are in some cases known from the literature or in Example I
~ XXIII can be obtained by methods known from the literature.

As mentioned above, the novel 5-membered heterocyclic compounds of general formula I and their addition salts, especially the inorganic or organic acids or bases and their physiologically acceptable addition salts, have valuable properties. Thus, A is an amino group optionally substituted at the nitrogen atom position, an aminoalkyl group, an amidino group, a guanidino group or a guanidinoalkyl group; or an amino group optionally substituted at the nitrogen atom position. A group which can be converted to an amidino group or a guanidino group in vivo as necessary, for example, an alkoxycarbonyl group, an alkenyloxycarbonyl group, an aralkoxycarbonyl group, an alkylcarbonyl group, an arylcarbonyl group, an aryloxycarbonyl at the position of a nitrogen atom. Group, alkanoyloxymethoxycarbonyl group, cycloalkanoyloxymethoxycarbonyl group, aralkanoyloxymethoxycarbonyl group, aryloxymethoxycarbonyl group, phosphono group, dialkylphosphoryl group or O-alkylphospho group A novel novel compound of the general formula I containing an amino group, an aminoalkyl group, an amidino group, a guanidino group or a guanidinoalkyl group substituted by a group, or a cyclic imino in which B is optionally substituted at the position of the nitrogen atom Represents a group, and -DE-
F is a carboxyl group, a sulfo group, a phosphono group, an O-alkyl-phosphono group or a 5-tetrazolyl group; or a carboxyl group, a sulfo group, a phosphono group, O- in vivo.
A group that can be converted into an alkyl-phosphono group or a tetrazolyl group, for example, an alkoxy group, an aralkoxy group, an aralkenyloxy group, a cycloalkylalkoxy group, a heteroarylalkoxy group, a pyrrolidin-2-one-1-
Ylalkoxy group, morpholinoalkoxy group, thiomorpholinoalkoxy group, 1-oxide-thiomorpholinoalkoxy group, cycloalkoxy group, benzocycloalkoxy group, bicycloalkoxy group, bicycloalkylalkoxy group, alkanoyloxymethoxy group, cycloalkylalkanoyloxymethoxy , A novel carbonyl group of general formula I containing a carbonyl group substituted by a group, an alkoxycarbonyloxymethoxy group, an aroyloxymethoxy group, an aralkanoyloxymethoxy group, an aryloxycarbonyloxymethoxy group or an aralkoxycarbonyloxymethoxy group. In addition to having beneficial pharmacological properties and inhibitory effects on inflammation and bone degeneration, the compounds have, inter alia, antithrombotic, anticoagulant and tumor or metastasis inhibitory effects. A.

Compounds of general formula I in which A represents a cyano group are
A valuable intermediate product for preparing the corresponding aminomethyl and amidino compounds of general formula I. For example, compounds of general formula I were investigated for their biological activity as follows.

1. Fibrinogen binding to human platelets Blood obtained by puncture of the antecubital vein is anticoagulated with trisodium citrate (final concentration: 13 mmol) and centrifuged at 170 xg for 10 minutes. Supernatant platelet-rich plasma was injected onto a Sepharose 2B column (Pharmacia) to yield 90 mM sodium chloride, 14 mM trisodium citrate, 5 mM glucose and 50 mM tris (hydroxymethyl). ) Elute with a solution of aminomethane (adjusted to pH 7.4). Gel-filtered platelets (GFP) that appear in front of plasma proteins are used for binding experiments. 50 μl of 60 mM calcium chloride solution, 50 μl of 0.6 mM adenosine diphosphate solution, 100 μl of substance solution or solvent and 50 μl of fibrinogen solution (containing 3 μg of ¹²⁵ I fibrinogen) are added to 750 μl of GFP and incubated for 20 minutes at ambient temperature. Non-specific binding is determined in the presence of cold fibrinogen 3 mg / ml.
Add 900 μl of the incubated material to the Eppendorf (E
ppendorf) Silicone oil in the tube (AP38: AR20, 1: 2v / v,
Carefully pipette into 250 μl Wacker Chemie and centrifuge for 2 minutes at 10,000 × g. The supernatant aqueous solution and some oil are drained, the tip of the tube is cut along with the platelet pellet, and the amount of bound fibrinogen is measured with a gamma counter. The concentration of a substance that produces 50% inhibition of fibrinogen binding was measured from a series of concentrations, indicated as IC _50.

2. Antithrombotic activity method. Platelet aggregation by the method of Born and Cross.
(J. Physiol. 170, 397 (1964)) in platelet-rich plasma collected from healthy subjects. Blood is mixed with 3.14% sodium citrate in a volume ratio of 1:10 to prevent clotting. The pattern of decrease in optical density in the collagen-induced aggregated platelet suspension is measured photometrically and recorded after addition of the substance that induces aggregation. The rate of aggregation is estimated from the angle of slope of the density curve. Calculate the optical density using the curve point with the highest light transmission. The amount of collagen used is as small as possible, but sufficient to obtain an irreversible reaction curve. Conventional commercial collagen manufactured by the Hormonchemie of Munich is used. Plasma is incubated with the substance for 10 minutes at 37 ° C. before addition of collagen. From the measurements obtained, the EC ₅₀ is determined graphically, which shows a 50% change in optical density with respect to the inhibition of aggregation. The table below contains the measured results.

[0088]

[Table 1]

[0089]

[Table 2]

[0090]

[Table 3] * ^125I was replaced with 3H- (3S, 5S) -5-[(4'-amidino-4-biphenylyl) -oxymethyl] -3-carboxymethyl-2-pyrrolidone.

The compounds of the present invention are well tolerated. This is because the animals did not die after the intravenous administration of 30 mg / kg of the compound of Example 1 (3) to 3 mice.
In view of their intercellular interactions or their inhibitory effects on cell-matrix interactions, the novel fused 5-membered heterocyclic compounds of general formula I and their physiologically acceptable addition salts are Suitable for treating or preventing the resulting disease or diseases in which cell-matrix interactions play a role,
For example, vein and artery thrombosis, cerebrovascular disease, pulmonary embolism,
It is suitable for treating or preventing heart failure, arteriosclerosis, osteoporosis and tumor metastasis, as well as for treating diseases or acquired diseases caused by the inheritance of cell-cell interactions or cell-solid structure interactions. They are also suitable for parallel treatment of thrombosis with vascular interventions such as thrombolytics or transluminal angioplasty, or treatment of shock, psoriasis, diabetes and inflammation.

For the treatment or prevention of the above-mentioned diseases, the dose is 0.1 μg / kg body weight, given up to 4 times daily.
-30 mg, preferably 1 μg-15 mg per kg body weight. For this purpose, the compounds of the formula I prepared according to the present invention may optionally comprise other active substances, for example thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, serotonin antagonists, α-receptor antagonists. , Alkyl nitrates such as glycerol trinitrate, phosphodiesterase inhibitors, prostacyclin and their analogs, thrombolytic agents such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatan sulfate. , An active protein C, vitamin K antagonist, hirudin, thrombin or other inhibitor of an active coagulation factor, in combination with one or more inert conventional carriers and / or diluents, such as peach Stiffness starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol,
Water / polyethylene glycol, propylene glycol,
Stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fats or suitable mixtures thereof together with the usual galenic preparations, such as simple or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories. Can be mixed. The following examples are intended to illustrate the invention.

[0093]

EXAMPLES Example I 4- [N- (4- amidino - benzoyl) - methyl amino] -3-nitro - From Ikikosan - [N-(3- Metokishika
Lubonyl-propyl) -amido] 4- [4- [N- (4-cyano-benzoyl) -methylamino] -3-nitro-benzoic acid- [N- (3-methoxycarbonyl-propyl) -amido] Prepared as in Example 3. R _f value: 0.11 (silica gel; ethyl acetate / ethanol =
7: 3) Similarly, the following compound is obtained. (1) 4- [N- (4-amidino-benzoyl) -methylamino] -3-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] _Rf value: 0.11 (silica gel; acetic acid Ethyl / ethanol =
(7: 3)

[0094] Example II 4- [N- (4- cyano - benzoyl) - methyl amino] -3-nitro - repose Kosan - [N-(3- Metokishika
Rubonyl-propyl) -amido] 2.84 g of N-ethyl- disopropylamine, while cooling to 0 ° C., 3.2 g of 4- [N- (4-cyano-benzoyl) -methylamino] -3-nitro-benzoyl chloride. ,
Add to a mixture of 1.68 g of methyl 4-aminobutyrate hydrochloride and 50 ml of methylene chloride. The mixture is stirred for 64 hours, returning to ambient temperature. Remove methylene chloride by evaporation,
The residue is purified on silica gel (eluent: ethyl acetate / ethanol = 200: 1). Yield: 3.9 g (100% of theory), R _f value: 0.62 (silica gel; ethyl acetate / ethanol =
9: 1) Similarly, the following compound is obtained. (1) 4- [N- (4-cyano-benzoyl) -methylamino] -3-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] _Rf value: 0.75 (silica gel; acetic acid Ethyl / ethanol =
9: 1) (2) Ethyl 4-[(4-cyano-phenyl) -oxymethylcarbonylamino] -3-nitro-phenoxy]-
Acetate 4-dimethylamino-pyridine is used as a base. Melting point: 151-153 ° C (3) 4- [2- (4-benzyl-piperazino) -ethylamino] -3- (4-cyano-benzoyl-amino)-
Benzoic acid- [N- (2-methoxycarbonyl-ethyl)
-Amide] The treatment is carried out in pyridine at ambient temperature. R _f value: 0.73 (silica gel; methylene chloride / methanol
= 9: 1, after developing twice) (4) 5- (4-cyano-benzoylamino) -2,4-
Bis-methylamino-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] The treatment is carried out using 4-dimethylamino-pyridine as base. Melting point: 208 to 210 ° C. R _f value: 0.71 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1, after three times development)

(5) 4-chloro-2-methoxy-5-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amido] 4-chloro-2-methoxy-5-nitro-benzoyl chloride, A mixture of β-alanine-methyl ester hydrochloride and toluene is refluxed for 48 hours. Melting point: 74-76 ° C R _f value: 0.43 (silica gel; methylene chloride / methanol
= 30: 1) (6) 6-methylamino-5-nitro-nicotinic acid- [N
-(2-Carboxy-ethyl) -amide] The treatment was carried out at room temperature with 1N NaOH, whereby 6-methylamino-5-nitro-dissolved in methylene chloride.
Nicotinic acid chloride (prepared from the acid and thionyl chloride) was added. R _f value: 0.47 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (7) same as 4-chloro-3-nitro-benzoic acid- (2-carboxy-pyrrolidide) (6) Use the operation. R _f value: 0.43 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 8: 2: 0.1) (8) Use the same procedure as for 4-chloro-3-nitro-benzoic acid- (3-carboxy-piperidide) (6). Melting point: 211-213 ° C. R _f value: 0.69 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 8: 2: 0.1)

[0096] EXAMPLE III 4- [N- (4- cyano - benzoyl) - methyl amino] -3-nitro - Ben Zoirukurorido 4- [N- (4- cyano - benzoyl) - methyl amino] -3-nitro - 6.2 g of benzoic acid and 20 ml of thionyl chloride
The mixture is refluxed until a clear solution forms. Excess thionyl chloride is evaporated off under reduced pressure and the residue is used without further purification. Similarly, the following compound is obtained. (1) 4-Chloro-2-methoxy-5-nitro-benzoyl chloride mixture is refluxed for 18 hours. The product is used without further purification.

[0097] EXAMPLE IV 4- [N- (4- cyano - benzoyl) - methyl amino] -3-nitro - repose Kosan methyl 4- [N- (4- cyano - benzoyl) - methyl amino] -3-nitro -9.9 g of benzoate, 290 ml of tetrahydrofuran and 290 ml of water with gentle heating.
29 ml of 1N lithium hydroxide solution
Is added with stirring at ambient temperature. The mixture further
After stirring for 25 minutes, 29 ml of 1N hydrochloric acid are added and tetrahydrofuran is distilled off under reduced pressure, after which the product is partially precipitated. The remaining aqueous phase is acidified with hydrochloric acid, extracted with ethyl acetate and another fraction is obtained after evaporation of ethyl acetate. The product is purified by absorption in hot tetrahydrofuran and precipitation with petroleum ether. Yield: 7.5 g (79% of theory), Melting point: 220-222 ° C. R _f value: 0.22 (silica gel; ethyl acetate / ethanol =)
9: 1)

Example V Methyl 4- [N- (4-cyano-benzoyl) -methylamino] -3-nitro -benzoate Methyl 4-methylamino-3-nitro-benzoate 1
A mixture of 3.1 g, 10.3 g of 4-cyano-benzoyl chloride and 75 ml of phosphorus oxychloride is stirred for 8 hours at 100 ° C.
After cooling, the mixture is destroyed with water and the aqueous phase is extracted with ethyl acetate. The ethyl acetate phase is washed with soda solution and concentrated by evaporation. The residue is dissolved in a little acetone and ether is added slowly. Discard the first settling amount (about 1.2 g). After adding more ether, the desired material is precipitated. Yield: 10.2 g (48% of theory), R _f value: 0.54 (silica gel; ethyl acetate / petroleum ether)
= 7: 3)

Example VI 5 (6) -amino-2- (4-cyano-phenyl) -beta
Nzoimidazole 2- (4-cyano-phenyl) -5 (6) -nitro-benzimidazole (4.8 g) was dissolved in a mixture of ethanol (150 ml) and dimethylformamide (20 ml), and 5% palladium /
1 g of charcoal is added and the mixture is treated with hydrogen at a pressure of 5 bar and ambient temperature. After 4 hours and 21 hours, the catalyst
Add 1 g. After a total of 24 hours, the catalyst is filtered off, the filtrate is evaporated down, the residue is taken up in ethyl acetate and extracted with 0.1N hydrochloric acid. Make the aqueous phase alkaline with sodium bicarbonate,
Extract with ethyl acetate. The residue remaining after evaporation of the ethyl acetate phase is triturated with water to form crystals. Yield: 1.6g (40% of theory), Melting point: 128-130 ° C (sintered from 118 ° C)

Similarly, the following compounds are obtained. (1) Ethyl 3-amino-4-[(4-cyano-phenyl) -oxymethylcarbonylamino] -phenoxy-
Acetate The solvent used is ethyl acetate and tetrahydrofuran 1: 3.
5 Mixture. _Rf value: 0.59 (silica gel; methylene chloride / methanol / glacial acetic acid = 50: 1: 0.1, after developing twice) (2) 3-amino-4- (3-thiomorpholino-propylamino) -benzoic acid- [N- (2-Methoxycarbonyl-ethyl) -amide] hydrochloride hydrochloride The treatment is carried out with 10% palladium / charcoal in methanol. R _f value: 0.67 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1, after developing twice) (3) 3-amino-4- (3-amino-propylamino)
-Benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] hydrochloride-hydrogen acetate The treatment is carried out with 10% palladium / charcoal in glacial acetic acid. R _f value: 0.23 (silica gel; methylene chloride / methanol / glacial acetic acid = 2: 1: 0.1, after developing twice) (4) 3-amino-4-methylamino-benzoic acid- [N-
(2-Methoxycarbonylethyl) -amide] Use the same procedure as (2). R _f value: 0.28 (silica gel; ethyl acetate / ethanol = 5
0: 2) (5) 3-Amino-4- [2- (3,4-dimethoxy-phenyl) -ethylamino] -benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] (2) Use the same operation as. R _f value: 0.53 (silica gel; ethyl acetate / ethanol = 5
(0: 2)

(6) 3-Amino-4- (3-pyridylmethylamino) -benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] The same procedure as (2) is used. R _f value: 0.07 (silica gel; ethyl acetate / ethanol =
9: 1) (7) 3-Amino-4-n-tetradecylamino-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] Use the same procedure as (2). R _f value: 0.55 (silica gel; ethyl acetate / ethanol = 5
0: 2) (8) 3-Amino-4- (3-methoxycarbonyl-propylamino) -benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amido] hydrochloride Add ethereal hydrochloric acid ( Use the same operation as 2). R _f value: 0.65 (silica gel; methylene chloride / methanol
= 9: 1) (9) 3-amino-4- (4-phenyl-butylamino)
-Benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] Use the same procedure as (2). R _f value: 0.68 (silica gel; ethyl acetate / ethanol =
9: 1) (10) 5-amino-2,4-bis-methylamino-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amido] hydrochloride salt The treatment was carried out in tetrahydrofuran with 10% palladium / charcoal. Done in. Melting point: 138 to 140 ° C. (decomposition) R _f value: 0.40 (silica gel; methylene chloride / methanol / concentrated ammonia = 19: 1: 0.1, after developing twice)

(11) 3-Amino-4-[(3,3-diphenyl-propyl) -amino] -benzoic acid- [N- (2-
Methoxycarbonyl-ethyl) -amide] using the same procedure as (2). R _f value: 0.69 (silica gel; ethyl acetate / ethanol =
9: 1) (12) 5-amino-6-methylamino-nicotinic acid- [N
-(2-Methoxycarbonyl-ethyl) -amide] Use the same procedure as (2). _Rf value: 0.77 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (13) 3-amino-4-methylamino-benzoic acid- (2-
Methoxycarbonyl-pyrrolidide) (2) The same procedure is used. R _f value: 0.41 (silica gel; ethyl acetate / ethanol =
9: 1) (14) 3-Amino-4-methylamino-benzoic acid- (3-
(Methoxycarbonyl-piperidide) Use the same procedure as (2). R _f value: 0.48 (silica gel; ethyl acetate / ethanol =
(7: 3)

Example VII 2- (4-Cyano-phenyl) -5 (6) -nitro-be
21.9 g of benzimidazole 3,4-diamino-nitrobenzene are added in several portions to 400 ml of phosphorus oxychloride with stirring at ambient temperature. Then 23.7 g of 4-cyano-benzoyl chloride are added. The mixture is first heated to 90 ° C. for 30 minutes and then to 100 ° C. for 6 hours. Most of the excess phosphorus oxychloride is evaporated off under reduced pressure, the residue is treated with water and the precipitate formed is taken up in ethyl acetate / water. The mixture is made alkaline with sodium bicarbonate and finally the organic phase is evaporated. Yield: 4.8 g (13% of theory), Melting point: higher than 200 ° C R _f value: 0.74 (silica gel; ethyl acetate / ethanol = 5)
(0: 2)

Example VIII Ethyl 4-amino-3-nitro-phenoxy-acetate
25 g of 4-amino-3-nitro-phenol was dissolved in 250 ml of dimethylformamide, and potassium tert. Butoxide was added.
18.5 g are added in several batches while cooling with ice. The mixture is stirred for a further 1.5 hours, then 18.5 ml of ethyl bromoacetate are added dropwise with water cooling and the mixture is stirred for a further 16 hours at ambient temperature. The solvent is evaporated off under reduced pressure, the residue is taken up with a mixture of 500 ml of ethyl acetate, 250 ml of tetrahydrofuran and 750 ml of water and the organic phase is washed with saturated saline solution. The aqueous phase is extracted with ethyl acetate, the organic phases are combined, evaporated and the residue is purified by column chromatography (neutral aluminum oxide; eluent: methylene chloride). Yield: 29g (75% of theory), Melting point: 110-113 ° C

Example IX 3-Amino-4- [2- (4-benzyl-piperazino)
- ethylamino] - From Ikikosan - [N-(2-Metokishika
Rubonyl-ethyl) -amido] 4- [2- (4-benzyl-piperazino) -ethylamino ] -3-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amido] dihydrochloride 6.3 g Is dissolved in a mixture of 100 ml of glacial acetic acid and 25 ml of water on a steam bath, and 4 g of iron powder is added.
Add within 10 minutes. Heat the mixture for another 30 minutes,
Filter through charcoal and evaporate the filtrate. The residue is taken up in 100 ml of tetrahydrofuran, applied to a silica gel column and eluted second with tetrahydrofuran. Fractions containing product are evaporated to dryness and triturated with water. The crystalline residue is filtered off, washed with water, washed with methanol and washed with ether. The product is processed further without further purification. Yield: 1.2 g (20% of theory), Melting point: 132-134 ° C (decomposition) R _f value: 0.63 (silica gel; methylene chloride / methanol)
= 8: 2)

[0106] Example X 4- [2- (4- benzyl - piperazino) - ethylamino] -3-nitro - From Ikikosan - [N-(2-Metokishika
Rubonyl-ethyl) -amido] dihydrochloride 4- [2- (4-benzyl-piperazino) -ethylamino ] -3-nitro-benzoic acid- [N- (2-carboxy-ethyl) -amide] 9.2 g Methanol while heating 1.
Suspend in 5 liters, cool to -20 ° C and thionyl chloride.
Mix with 1.7 ml, hold at -10 ° C for 2 hours and then stir at ambient temperature for 16 hours. The mixture is evaporated under reduced pressure to 150 ml, the crystals are filtered off, washed with methanol and washed with ether. Yield: 6.5 g (64% of theory), Melting point: 225-227 ° C (decomposition) _Rf value: 0.43 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.1)

Similarly, the following compounds are obtained. (1) 3-Nitro-4- (3-thiomorpholino-propylamino) -benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] hydrochloride Etheric hydrochloric acid was added and the treatment was performed with methanol. At ambient temperature in. R _f value: 0.59 (silica gel; methylene chloride / methanol / concentrated ammonia = 19: 1: 0.1, after developing twice) (2) 4- (3-amino-propylamino) -3-nitro-benzoic acid- [ N- (2-Methoxycarbonyl-ethyl) -amido] hydrochloride (1) The same procedure is used. Melting point: 178-180 ° C (decomposition) _Rf value: 0.41 (silica gel; n-butanol / glacial acetic acid /
Water = 4: 1: 1) (3) 4-methylamino-3-nitro-benzoic acid- [N-
(2-Methoxycarbonyl-ethyl) -amide] Use the same procedure as (1). Melting point: 125 to 127 ° C. R _f value: 0.35 (silica gel; ethyl acetate / ethanol = 5
0: 1) (4) 4- [2- (3,4-dimethoxy-phenyl) -ethylamino] -3-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] (1) Use the same operation as. Melting point: 112-115 ° C. R _f value: 0.71 (silica gel; ethyl acetate / ethanol = 5
0: 2) (5) 3-nitro-4- (3-pyridylmethylamino)-
Benzoic acid- [N- (2-methoxycarbonyl-ethyl)
-Amide] Use the same procedure as (1). R _f value: 0.59 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

(6) 3-Nitro-4-n-tetradecylamino-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] The same procedure as in (1) is used. R _f value: 0.78 (silica gel; ethyl acetate / ethanol = 5
0: 2) (7) 4- (3-methoxycarbonyl-propylamino)
-3-Nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] Use the same procedure as (1). R _f value: 0.80 (silica gel; methylene chloride / methanol
= 9: 1) (8) 3-amino-2-benzylamino-benzoic acid- [N
-(2-Methoxycarbonyl-ethyl) -amide] Use the same procedure as (1). R _f value: 0.69 (silica gel; methylene chloride / methanol
= 9: 1) (9) 3-nitro-4- (4-phenyl-butylamino)
-Benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] Use the same procedure as (1). R _f value: 0.84 (silica gel; ethyl acetate / ethanol =
9: 1) (10) 2,4-Bis-methylamino-5-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amido] hydrochloride The same procedure is used as for (1). R _f value: 0.51 (silica gel; methylene chloride / methanol
= 19: 1)

(11) 3-Amino-4- [2- (4-amino-3,5-dibromo-phenyl) -ethylamino) -benzoic acid- [N- (2-methoxycarbonyl-ethyl)-
Amide] hydrochloride using the same procedure as (1). Melting point: 135 to 140 ° C. (decomposition) R _f value: 0.73 (silica gel; ethyl acetate / ethanol =
8: 2) (12) 4-[(3,3-diphenyl-propyl) -amino] -3-nitro-benzoic acid- [N- (2-methoxycarbonyl-ethyl) -amide] Same operation as (1) To use. R _f value: 0.86 (silica gel; ethyl acetate / ethanol =
9: 1) (13) 6-methylamino-5-nitro-nicotinic acid- [N
-(2-Methoxycarbonyl-ethyl) -amide] Use the same procedure as (1). _Rf value: 0.30 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (14) 4-methylamino-3-nitro-benzoic acid- (2-
Methoxycarbonyl-pyrrolidide] (1) is used. R _f value: 0.57 (silica gel; ethyl acetate / ethanol =
9: 1) (15) 4-methylamino-3-nitro-benzoic acid- (3-
Methoxycarbonyl-piperidide) Use the same procedure as (1). R _f value: 0.67 (silica gel; ethyl acetate / ethanol =
9: 1)

[0110] Example XI 4- [2- (4- benzyl - piperazino) - ethylamino] -3-nitro - From Ikikosan - [N-(2-carboxy
-Ethyl) -amide] 4-chloro-3-nitro-benzoic acid- [N- (2-carboxy-ethyl) -amide] 8.2 g (4-chloro-3-nitro-benzoyl chloride and β-alanine-methyl ester , Followed by saponification with 48% hydrobromic acid), 6.6 g of 2- (4-benzyl-piperazino) -ethylamine (potassium tert. Butoxide and 1-benzyl-piperazine in ethanol. 2-Bromo-ethylamine prepared from hydrobromide), triethylamine
Heat 4.2 ml and 25 ml water on a steam bath for 8 hours. The mixture is evaporated and purified by column chromatography (silica gel; methylene chloride / methanol / glacial acetic acid = 8: 2: 0.1 to 2: 1: 0.1). Yield: 9.2 g (67% of theory), R _f value: 0.47 (silica gel; methylene chloride / methanol / concentrated ammonia = 8: 2: 0.1)

Similarly, the following compounds are obtained. (1) 3-Nitro-4- (3-thiomorpholino-propylamino) -benzoic acid- [N- (2-carboxy-ethyl) -amide] Melting point: 207 to 211 ° C (decomposition) R _f value: 0.33 ( Silica gel; methylene chloride / methanol / concentrated ammonia = 8: 2: 0.1, after developing 4 times) (2) 4- (3-amino-propylamino) -3-nitro-benzoic acid- [N- (2-carboxy -Ethyl) -amide] The treatment is carried out without the auxiliary base using twice the molar amount of 1,3-diaminopropane. Melting point: 136 ° C. (decomposition, sintering from 118 ° C.) R _f value: 0.35 (silica gel; isopropanol / water / concentrated ammonia = 7: 2: 1) (3) 4-methylamino-3-nitro-benzoic acid- [ N-
(2-Carboxy-ethyl) -amide] The treatment is carried out using 40% methylamine solution as solvent and the mixture is heated in a bomb at 50 ° C. for 8 hours. Melting point: 187 to 190 ° C. R _f value: 0.22 (silica gel; ethyl acetate / ethanol = 5
0: 1) (4) 4- [2- (3,4-dimethoxy-phenyl) -ethylamino] -3-nitro-benzoic acid- [N- (2-carboxy-ethyl) -amide] hydrochloride its treatment Is performed at a bath temperature of 90 ° C. without the use of solvents or auxiliary bases. Melting point: 105 to 107 ° C. R _f value: 0.35 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 9: 1: 0.01) (5) 3-nitro-4- (3-pyridylmethylamino)-
Benzoic acid- [N- (2-carboxy-ethyl) -amide] The treatment is carried out without auxiliary base with 3 volumes of 3-picolylamine. Melting point: 110 ° C (sintered from 95 ° C) R _f value: 0.64 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

(6) 3-Nitro-4-n-tetradecylamino-benzoic acid- [N- (2-carboxy-ethyl)-
Amide] The treatment is carried out without using a solvent. R _f value: 0.59 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 9: 1: 0.02) (7) 4- (3-carboxy-propylamino) -3-nitro-benzoic acid- [N- (2-carboxy-ethyl)-
Amide] Potassium hydrogen carbonate is added and the treatment is performed in water. R _f value: 0.42 (silica gel; methylene chloride / methanol
= 9: 1) (8) 4-benzylamino-3-nitro-benzoic acid- [N
-(2-Carboxy-ethyl) -amide] The treatment is carried out without solvent. R _f value: 0.76 (silica gel; methylene chloride / methanol
= 9: 1) (9) 3-nitro-4- (4-phenyl-butylamino)
-Benzoic acid- [N- (2-carboxy-ethyl) -amide] The treatment was carried out in the absence of solvent as N- as auxiliary base.
Performed using ethyl-diisopropylamine. R _f value: 0.42 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 9: 1: 0.02)

(10) 2,4-bis-methylamino-5-nitro-benzoic acid- [N- (2-carboxy-ethyl)-
Amido] methylamine salt The treatment was similar to (3) using 4-chloro-2-methoxy-5-nitro-benzoic acid- [N- (2-carboxy-ethyl) -amide] as starting material. The reaction lasts 12 hours. Melting point: 180 to 189 ° C. (decomposition) R _f value: 0.62 (silica gel; methylene chloride / methanol / glacial acetic acid = 19: 1: 0.1) (11) 4- [2- (4-amino-3,
5-Dibromo-phenyl) -ethylamino] -3-nitro-benzoic acid- [N- (2-carboxy-ethyl) -amide] (7) The same procedure is used. Melting point: 110-115 ° C. R _f value: 0.65 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 7: 3: 0.02) (12) 4-[(3,3-diphenyl-propyl) -amino] -3-nitro-benzoic acid- [N- (2-carboxy-ethyl) -amide] (9 ) Is used. Melting point: 185 ° C (sintered from 165 ° C) R _f value: 0.59 (silica gel; ethyl acetate / ethanol /
Glacial acetic acid = 9: 1: 0.02) (13) 4-methylamino-3-nitro-benzoic acid- (2-
Carboxy-pyrrolidide) Use the same procedure as (3). R _f value: 0.12 (silica gel; ethyl acetate / ethanol =
9: 1) (14) 4-methylamino-3-nitro-benzoic acid- (3-
Carboxy-piperidide) Use the same procedure as (3). R _f value: 0.33 (silica gel; ethyl acetate / ethanol =
9: 1)

Example XII 3-Amino-4-benzylamino-benzoic acid- [N-
(2-carboxy - ethyl Le) - amide] 4-benzylamino-3-nitro - acid - [N-
4.0 g of (2-carboxy-ethyl) -amide] are dissolved in 5% sodium hydroxide solution by heating and 5.0 g of sodium dithionite are added in several portions. After decolorizing the solution, it is stirred for a further 15 minutes, cooled and the precipitate formed is filtered off. The filtrate is made weakly acidic with 2N hydrochloric acid, after which the product is precipitated. It is suction filtered and washed with water. Yield: 1.6 g (52% of theory), R _f value: 0.26 (silica gel; methylene chloride / methanol)
= 9: 1) Similarly, the following compound is obtained. (3) 3-Amino-4- [2- (4-amino-3,5-dibromo-phenyl) -ethylamino] -benzoic acid- [N
-(2-Carboxy-ethyl) -amido] hydrochloride Melting point: 150 to 155 ° C R _f value: 0.22 (silica gel; ethyl acetate / ethanol =
8: 2)

Example XIII 4-Chloro-2-methoxy-5-nitro-benzoic acid-
[N- (2-Carboxy -ethyl) -amide] The same procedure as in Example 17 is used. Melting point: 170 to 172 ° C. R _f value: 0.38 (silica gel; methylene chloride / methanol / glacial acetic acid = 30: 1: 0.1, after developing twice)

[0116] Example 1 2- (4-amidino-phenyl) - -5 - [(3-carboxy - propyl) - amino carbonyl] -1-methyl -
Benzimidazole 2- (4-amidino-phenyl) -5-[(3-methoxy-carbonyl-propyl) -aminocarbonyl] -1
A mixture of 2.0 g of methyl-benzimidazole, 20 ml of methanol and 15.8 ml of 1N sodium hydroxide solution is stirred for 16 hours at ambient temperature. It is evaporated under reduced pressure, taken up with water and neutralized by addition of ammonium chloride. The precipitate formed is filtered off. Yield: 1.3 g (68% of theory), Melting point: higher than 215 ° C R _f value: 0.75 (reverse phase plate RP18; methanol / 5% sodium chloride aqueous solution = 6: 4)

Similarly, the following compounds are obtained. (1) 2- (4-amidino-phenyl) -5 (6)-
[(2-carboxy-ethyl) -carbonyl-amino]
-Benzimidazole Melting point: higher than 200 ° C R _f value: 0.63 (reverse phase plate RP18; methanol / 5% sodium chloride aqueous solution = 6: 4) Calculated value x3 H ₂ O: C 53.46 H 5.73 N 17.31 Found value: 53.67 5.54 17.29 (2) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -aminocarbonyl]-
Benzimidazole hydrochloride Lithium hydroxide is used. R _f value: 0.26 (silica gel; methylene chloride / methanol
= 7: 3) (3) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole Melting point: 247 to 249 ° C R _f value: 0.70 (Reverse phase plate RP18; methanol / 5% sodium chloride aqueous solution = 6: 4) (4) 2- (4-amidino-phenyl) -5 (6)-
[(3-Carboxy-propyl) -carbonyl-amino] -benzimidazole (5) 2- (4-aminomethyl-phenyl) -5-[(3
-Carboxy-propyl) -aminocarbonyl] -1-
Methyl-benzimidazole

(6) 2- (4-aminomethyl-phenyl)
-5 (6)-[(2-carboxy-ethyl) -amino-
Carbonyl] -benzimidazole (7) 2- (4-aminomethyl-phenyl) -5-[(2
-Carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (8) 2- (4-amidino-phenyl) -6-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (9) 2- (4-Amidino-phenyl) -5-[(3-carboxy-propyl) -carbonyl] -1-methyl-benzimidazole (10) 2- (4-amidino-phenyl) -5-[( 4-Carboxy-butyl) -carbonyl] -1-methyl-benzimidazole (11) 2- [4- (2-amino-ethyl) -phenyl]-
5-[(3-carboxy-propyl) -carbonyl]-
1-Methyl-benzimidazole (12) 2- (4-guanidinomethyl-phenyl) -5-
[(2-Carboxy-ethyl) -carbonyl] -1-methyl-benzimidazole (13) 5-[(3-carboxy-propyl) -aminocarbonyl] -2- (3-guanidino-phenyl) -1-methyl- Benzimidazole (14) 2- [4- (2-amino-ethyl) -phenyl]-
5-[(2-carboxy-ethyl) -carbonyl] -1
-Methyl-benzimidazole (15) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -thio] -benzimidazole (16) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -sulfinyl] -benzimidazole (17) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -sulfonyl] -benzimidazole (18) 2- (4-amidino-phenyl) -5 (6)-
[(3-Carboxy-propyl) -thio] -benzimidazole (19) 2- (4-amidino-phenyl) -5 (6)-
[(3-Carboxy-propyl) -sulfinyl] -benzimidazole

(20) 2- (4-amidino-phenyl) -5
(6)-[(3-Carboxy-propyl) -sulfonyl] -benzimidazole (21) 2- (4-amidino-phenyl) -5 (6)-
[(3-Carboxy-propyl) -amino] -benzimidazole (22) 5 (6)-[N-acetyl-N- (3-carboxy-propyl) -amino] -2- (4-amidino-phenyl)- Benzimidazole (23) 2- (4-amidino-phenyl) -5 (6)-
[(3-Carboxy-propyl) -oxy] -benzimidazole (24) 2- (4-amidino-phenyl) -5 (6)-(4
-Carboxy-butyl) -benzimidazole (25) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -aminomethyl] -benzimidazole (26) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -thiomethyl] -benzimidazole (27) 2- (4-amidino-phenyl) -5 (6)-
[(2-Carboxy-ethyl) -sulfinyl-methyl] -benzimidazole (28) 2- (4-amidino-phenyl) -5 (6)-
[(2-carboxy-ethyl) -sulfonyl-methyl]
-Benzimidazole (29) 5 (6)-[N-acetyl-N- (2-carboxy-ethyl) -aminomethyl] -2- (4-amidino-phenyl) -benzimidazole

(30) 2- (4-amidino-phenyl) -5
(6)-(Carboxymethylcarbonyl-amino-methyl) -benzimidazole (31) 2- (4-amidino-phenyl) -5 (6)-(4
-Carboxy-1-buten-1-yl) -benzimidazole (32) 2- (4-amidino-phenyl)-[(2-carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [4,5- b] Pyridine R _f value: 0.74 (reverse phase plate RP18; methanol / 5% sodium chloride aqueous solution = 6: 4) (33) 2- (4-amidino-phenyl) -6-[(2-carboxy-ethyl)- Aminocarbonyl] -imidazo [4,5-b] pyridine (34) 2- (4-amidino-phenyl) -6-[(2-carboxy-ethyl) -aminocarbonyl] -imidazo [1,2-a] pyridine (35) 2- (4-Amidino-phenyl) -6-[(2-carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [4,5-c] pyridine (36) 2- (4-amidino -Phenyl) -6-[( 2-Carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [4,5-b] pyridine (37) 2- (4-amidino-phenyl) -6-[(2-carboxy-ethyl) -aminocarbonyl ] -Imidazo [4,5-c] pyridazine (38) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -imidazo [4,5-b] pyrazine (39 ) 8- (4-Amidino-phenyl) -2-[(2-carboxy-ethyl) -aminocarbonyl] -9-methyl-purine

(40) 8- (4-amidino-phenyl) -2
-[(2-carboxy-ethyl) -aminocarbonyl]
-6-Chloro-9-methyl-purine (41) 8- (4-amidino-phenyl) -2-[(2-carboxy-ethyl) -aminocarbonyl] -6-methoxy-9-methyl-purine (42) 8- (4-Amidino-phenyl) -2-[(2-carboxy-ethyl) -aminocarbonyl] -6-dimethylamino-9-methyl-purine (43) 8- (4-amidino-phenyl) -6- Amino-2
-[(2-carboxy-ethyl) -aminocarbonyl]
-9-Methyl-purine (44) 8- (4-amidino-phenyl) -2-[(2-carboxy-ethyl) -aminocarbonyl] -9-methyl-6-piperidino-purine (45) 8- (4 -Amidino-phenyl) -2-[(2-carboxy-ethyl) -aminocarbonyl] -9-methyl-hypoxanthine (46) 2- (4-amidino-phenyl) -6-[(2-carboxy-ethyl) -Aminocarbonyl] -imidazo [1,2-a] pyrimidine (47) 2- (4-amidino-phenyl) -5- [N- (2
-Carboxy-ethyl) -methyl-aminocarbonyl]
-1-Methyl-benzimidazole (48) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -7-fluoro-1-methyl-benzimidazole (49) 2- (4-Amidino-phenyl) -6-[(2-carboxy-ethyl) -aminocarbonyl] -4-chloro-benzimidazole

(50) 2- (4-amidino-phenyl) -4
-Bromo-6-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole (51) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -6- Hydroxy-1-methyl-benzimidazole (52) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -6-methoxy-1-methyl-benzimidazole (53) 2 -(4-Amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-6-propyloxy-benzimidazole (54) 2- (4-amidino-phenyl) -6- [(2-Carboxy-ethyl) -aminocarbonyl] -4-methyl-benzimidazole (55) 2- (4-amidino-phenyl) -5-[(2-carboxy -Ethyl) -aminocarbonyl] -1-methyl-6-methanesulfonylamino-benzimidazole (56) 6-acetylamino-2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -amino Carbonyl] -1-methyl-benzimidazole (57) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -6-dimethylamino-1-methyl-benzimidazole (58) ) 2- (4-Amidino-phenyl) -1-n-butyl-5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole (59) 2- (4-amidino-phenyl) -5- [ (2-Carboxy-ethyl) -aminocarbonyl] -1-n-decyl-benzimidazole

(60) 2- (4-amidino-phenyl) -5
-[(2-carboxy-ethyl) -aminocarbonyl]
-1-Cyclopropyl-benzimidazole (61) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-cyclohexyl-benzimidazole (62) 2- (4- Amidino-phenyl) -1-benzyl-
5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole hydrochloride _Rf value: 0.25 (silica gel; methylene chloride / methanol)
= 8: 2) (63) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Phenyl-propyl) -benzimidazole (64) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
(3,4-Dimethoxy-phenyl) -ethyl] -benzimidazole (65) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
(2-Pyridyl) -ethyl] -benzimidazole (66) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Pyridyl-methyl) -benzimidazole (67) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (4-
Pyridyl-methyl) -benzimidazole (68) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [3-
(1-Imidazolyl) -propyl] -benzimidazole (69) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
(4-Imidazolyl) -ethyl] -benzimidazole

(70) 2- (4-amidino-phenyl) -5
-[(2-carboxy-ethyl) -aminocarbonyl]
-1- (2-Piperazino-ethyl) -benzimidazole (71) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (2-
Piperidino-ethyl) -benzimidazole (72) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Morpholino-propyl) -benzimidazole (73) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Thiomorpholino-propyl) -benzimidazole Lithium hydroxide in tetrahydrofuran / water is used. R _f value: 0.06 (silica gel; methylene chloride / methanol / concentrated ammonia = 2: 1: 0.1, after developing twice) (74) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl ) -Aminocarbonyl] -1- [3-
(S-Oxide-thiomorpholino) -propyl] -benzimidazole Lithium hydroxide in tetrahydrofuran / water is used. R _f value: 0.28 (silica gel; n-butanol / glacial acetic acid /
Water = 4: 1: 2, after developing 3 times) (75) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [3-
(S, S-dioxide-thiomorpholino) -propyl]
-Benzimidazole Use lithium hydroxide in tetrahydrofuran / water. R _f value: 0.14 (silica gel; isopropanol / water / concentrated ammonia = 7: 2: 1, after developing twice)

(76) 2- (4-amidino-phenyl) -1
-(3-Amino-propyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole diacetate salt Lithium hydroxide in tetrahydrofuran / water is used. Melting point: Decomposition from 110 ° C. R _f value: 0.13 (silica gel; isopropanol / water / concentrated ammonia = 7: 2: 1) (77) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -Aminocarbonyl] -1- (2-
Hydroxy-ethyl) -benzimidazole (78) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (2-
Methoxy-ethyl) -benzimidazole (79) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole-3-oxide Melting point: 263-265 ℃ (decomposition) R _f value: 0.79 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

(80) 1-allyl-2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -amino-carbonyl] -benzimidazole (81) 2- (4-amidino-phenyl) -5-[(2-Carboxy-ethyl) -aminocarbonyl] -1-phenyl-benzimidazole (82) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl]- 1- (4-
Chloro-phenyl) -benzimidazole (83) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (4-
Methoxy-phenyl) -benzimidazole (84) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Methyl-phenyl) -benzimidazole (85) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Pyridyl) -benzimidazole (86) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Methylsulfenyl-phenyl) -benzimidazole (87) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Methylsulfinyl-phenyl) -benzimidazole (88) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Methylsulfonyl-phenyl) -benzimidazole (89) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-carboxymethyl-benzimidazole

(90) 2- (4-amidino-phenyl) -1
-(2-Carboxy-ethyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole (91) 2- (4-amidino-phenyl) -1- (2-aminocarbonyl-ethyl)- 5-[(2-Carboxy-ethyl) -aminocarbonyl] -benzimidazole (92) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (2-
Dimethylaminocarbonyl-ethyl) -benzimidazole (93) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (2-
Morpholinocarbonyl-ethyl) -benzimidazole (94) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (2-
Thiomorpholinocarbonyl-ethyl) -benzimidazole (95) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
(S-Oxide-thiomorpholinocarbonyl) -ethyl] -benzimidazole (96) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
(S, S-dioxide-thiomorpholinocarbonyl)-
Ethyl] -benzimidazole (97) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
(Carboxymethyl-aminocarbonyl) -ethyl]-
Benzimidazole (98) 2- (4-aminomethyl-cyclohexyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1-Methyl-benzimidazole (99) 2- (1-amidino-4-piperidinyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1-methyl-benzimidazole

(100) 2- (5-amidino-2-pyridyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (101) 2- (4-amidino-2) -Fluoro-phenyl)
-5-[(2-Carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (102) 2- (4-amidino-2-chloro-phenyl)-
5 (6)-[(2-Carboxy-ethyl) -aminocarbonyl] -benzimidazole (103) 2- (4-amidino-2-methoxy-phenyl)
-5-[(2-Carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (104) 2- (4-amidino-2-methyl-phenyl)-
5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (105) 2- (4-amidino-phenyl) -5- (4-carboxy-1-piperidinyl) -3-methyl- Imidazo [4,5-b] pyridine (106) 2- (4-amidino-phenyl) -5- (4-carboxymethyl-1-piperidinyl) -3-methyl-imid [4,5-b] pyridine (107) ) 2- (4-Amidino-phenyl) -5- (4-carboxy-cyclohexylmethylamino) -3-methyl-imida [4,5-b] pyridine (108) 2- (4-amidino-phenyl) -5 -[(2-
Carboxy-ethyl) -aminocarbonyl] -benzoxazole (109) 2- (4-amidino-phenyl) -6-[(2-
Carboxy-ethyl) -aminocarbonyl] -benzothiazole

(110) 2- (4-amidino-phenyl)-
5-[(2-Carboxy-ethyl) -aminocarbonyl] -oxazolo [5,4-b] pyridine (111) 2- (4-amidino-phenyl) -5- (N-carboxymethyl-methylaminocarbonylmethyl) -5
H-imidazo [4,5-c] pyridin-4-one (112) 8- (4-amidino-phenyl) -1- (N-carboxymethyl-methylaminocarbonylmethyl) -hypoxanthine (113) 8- ( 4-Amidino-phenyl) -1- (N-carboxymethyl-methylaminocarbonylmethyl) -xanthine (114) 2- (4-amidino-phenyl) -6-[(2-
Carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [1,2-a] pyridine (115) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- (2
-Pyrrolidino-ethyl) -benzimidazole (116) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- (3
-Methylsulfenyl-propyl) -benzimidazole (117) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- (3
-Methylsulfinyl-propyl) -benzimidazole (118) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- (3
-Methylsulfonyl-propyl) -benzimidazole (119) 2- (4-amidino-1-piperazinyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1-methyl-benzimidazole

(120) 2- (4-amidino-phenyl)-
5-[(2-Carboxy-ethyl) -aminocarbonyl] -1-propargyl-benzimidazole (121) 2- (4-amidino-phenyl) -6- [N-
(3-Carboxy-propyl) -methanesulfonylamino] -3-methyl-imidazo [4,5-b] pyridine (122) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminosulfonyl] -1-methyl-benzimidazole (123) 2- (4-amidino-phenyl) -5- (carboxymethyl-aminosulfonyl) -1-methyl-benzimidazole (124) 2- ( 4-amidino-phenyl) -5- [N-
[(4-Carboxy-cyclohexyl) -methyl] -N
-Methyl-amino] -3-methyl-imidazo [4,5-
b] Pyridine (125) 2- (4-amidino-phenyl) -5- (4-carboxymethyl-1-piperazinyl) -3-methyl-imidazo [4,5-b] pyridine (126) 2- (4- Amidino-phenyl) -5- (4-carboxymethyl-3-oxo-1-piperazinyl) -3
-Methyl-imidazo [4,5-b] pyridine (127) 5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-2- (4-methylamidino-phenyl) -benzimidazole (128) 2- (n-butylamidino-phenyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1-Methyl-benzimidazole (129) 5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-2- (4-methylaminomethyl-phenyl) -benzimidazole

(130) 2- (4-amidino-phenyl)-
5-[(4-carboxy-cyclohexyl) -amino]
-3-Methyl-imidazo [4,5-b] pyridine (131) 2- (4-amidino-phenyl) -5- [N-
(2-Carboxy-ethyl) -methyl-aminosulfonyl] -1-methyl-benzimidazole (132) 2- (4-amidino-cyclohexyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1-Methyl-benzimidazole (133) 8- (4-amidino-phenyl) -1- (N-carboxymethyl-methylaminocarbonylmethyl) -3
-Methyl-xanthine (134) 2- (4-amidino-phenyl) -1- (6-amino-hexyl) -5-[(2-carboxy-ethyl)
-Aminocarbonyl] -benzimidazole (135) 2-[(4-amidino-phenyl) -oxymethyl] -5 (6) -carboxymethoxy-benzimidazole R _f value: 0.07 (silica gel; n-butanol / glacial acetic acid /
Water = 4: 1: 1, after developing twice) Calculated value: C 60.00 H 4.74 N 16.46 Measured value: 59.60 4.82 16.52 (136) 2- (4-amidino-phenyl) -1- [2-
(4-Benzyl-piperazino) -ethyl] -5-[(2
-Carboxy-ethyl) -aminocarbonyl] -benzimidazole Lithium hydroxide in tetrahydrofuran / water is used. Melting point: 82 ° C (decomposition) R _f value: 0.51 (silica gel; isopropanol / water / concentrated ammonia = 7: 2: 1)

(137) 2- (4-amidino-phenyl)-
5-[(2-Carboxy-ethyl) -aminocarbonyl] -1- (3-thiomorpholino-propyl) -benzimidazole Lithium hydroxide in tetrahydrofuran / water is used. _Rf value: 0.50 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 10) (138) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- (3
-Carboxy-propyl) -benzimidazole R _f value: 0.10 (silica gel; methylene chloride / methanol)
= 8: 2) (139) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1-methyl-6-methylamino-benzimidazole lithium hydroxide is used. Melting point: 265-266 ° C (decomposition) _Rf value: 0.35 (silica gel; n-butanol / glacial acetic acid /
Water = 4: 1: 2) (140) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -6- (N
-Carboxymethyl-methylamino) -1-methyl-benzimidazole Lithium hydroxide is used. R _f value: 0.62 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4, after developing twice)

(141) 2- (4-amidino-phenyl)-
5-[(2-Carboxy-ethyl) -aminocarbonyl] -1- (3,3-diphenyl-propyl) -benzimidazole (142) 2- [4- (2-amino-2-propyl) -phenyl]- 5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (143) 2- (1-amino-5-indanyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1-Methyl-benzimidazole (144) 2- (1-amino-1,2,3,4-tetrahydro-6-naphthyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl- Benzimidazole (145) 2- [4- (1-amino-cyclopropyl) -phenyl] -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (146) 2- [4 -(1-Amino-cyclopentyl) -phenyl] -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (147) 2- (4-amidino-phenyl) -5-[( 2-
Carboxy-2-methyl-propyl) -aminocarbonyl] -1-methyl-benzimidazole (148) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-propyl) -aminocarbonyl] -1-methyl-benzimidazole (149) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-4-phenyl-butyl) -aminocarbonyl] -1-methyl-benzimidazole

(150) 8- (4-amidino-phenyl)-
2-[(2-carboxy-ethyl) -aminocarbonyl] -7-methyl-purine (151) 8- (4-amidino-phenyl) -2-[(2-
Carboxy-ethyl) -aminocarbonyl] -6-methoxy-7-methyl-purine (152) 8- (4-amidino-phenyl) -2-[(2-
Carboxy-ethyl) -aminocarbonyl] -6-dimethylamino-7-methyl-purine (153) 8- (4-amidino-phenyl) -6-amino-
2-[(2-carboxy-ethyl) -aminocarbonyl] -7-methyl-purine (154) 8- (4-amidino-phenyl) -2-[(2-
Carboxy-ethyl) -aminocarbonyl] -7-methyl-6-piperidino-purine (155) 8- (4-amidino-phenyl) -2-[(2-
Carboxy-ethyl) -aminocarbonyl] -7-methyl-hypoxanthine (156) 2- (4-amidino-phenyl) -7-[(2-
Carboxy-ethyl) -aminocarbonyl] -imidazo [1,2-a] pyridine (157) 2- (4-amidino-phenyl) -7-[(2-
Carboxy-ethyl) -aminocarbonyl] -imidazo [1,2-a] pyrimidine (158) 2- (4-amidino-phenyl) -7-[(2-
Carboxy-ethyl) -aminocarbonyl] -imidazo [1,2-c] pyrimidine (159) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -benzothiazole

(160) 8- (4-amidino-phenyl)-
1- (4-carboxy-butyl) -3,9-dimethyl-
Xanthine Melting point: 263-265 ° C (decomposition) _Rf value: 0.48 (silica gel; n-butanol / glacial acetic acid /
Water = 4: 1: 1.5) (161) 2- (4-amidino-phenyl) -7-[(2-
Carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [1,2-a] pyridine (162) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1-methyl-6- (3-phenyl-propyloxy) -benzimidazole (163) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- (4
-Methyl-benzyl) -benzimidazole (164) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1- [2
-(3,5-Dichloro-4-hydroxy-phenyl)-
Ethyl] -benzimidazole (165) 2- (4-amidino-phenyl) -5-[(2-
Carboxy-ethyl) -aminocarbonyl] -1-
[(2-Phenyl-ethyl) -aminocarbonylmethyl] -benzimidazole

[0136] Example 2 2- (4-amidino-phenyl) - -5 - [(3-methoxycarbonyl - propyl Le) - aminocarbonyl] -1-
Methyl-benzimidazole hydrochloride methyl 4- [4- [N- (4-amidino-benzoyl)
-Methylamino] -3-nitro-benzoylamino]-
4.2 g of butyrate are dissolved in 100 ml of methanol, mixed with 10 ml of ethereal hydrochloric acid and 0.5 g of 10% palladium / charcoal and treated with 5 bar of hydrogen for 22 hours at ambient temperature.
Another 0.3 g of catalyst is added and the mixture is left to react for another hour. The catalyst is filtered off, the filtrate is evaporated and the residue at ambient temperature for 1 hour 100 ml ethyl acetate and 10 ml methanol.
Stir with a mixture of and then obtain the material in crystalline form. Yield: 3.7 g (100% of theory), Melting point: higher than 200 ° C R _f value: 0.65 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

Similarly, the following compounds are obtained. (1) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Methyl-benzimidazole _Rf value: 0.59 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (2) 2- (4-amidino-phenyl) -5-[(2-ethoxycarbonyl- Ethyl) -aminocarbonyl] -1
-Methyl-benzimidazole (3) 2- (4-amidino-phenyl) -5- [N- (2
-Methoxycarbonyl-ethyl) -N-methyl-aminocarbonyl] -1-methyl-benzimidazole (4) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]- 1
-Methyl-benzimidazol-3-oxide The treatment is carried out without the addition of hydrochloric acid. R _f value: 0.63 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

Example 3 2-[(4-amidino-phenyl) -oxymethyl]-
5 (6) - Metokishika carbonyl - methoxy - Benzoimi
Dazole hydrochloride 2-[(4-cyano-phenyl) -oxymethyl] -5
2.4 g of (6) -methoxycarbonylmethoxy-benzimidazole is suspended in 300 ml of methanol. Hydrochloric acid gas was piped into the mixture at 0-10 ° C for 1 hour and the resulting mixture was stirred at 15-20 ° C for 4 hours. The methanol is evaporated off under reduced pressure, the residue is mixed with 75 ml of methanol and this is in turn distilled off under reduced pressure. Methanol residue
Suspended in 300 ml, then 16.3 g ammonium carbonate was added in several portions with stirring, and the mixture was stirred for another 16
Stir for hours. The reaction mixture was mixed with 3 parts of methanol and 1
The pH is adjusted to 4 with a mixture of parts of concentrated hydrochloric acid. It is evaporated to dryness and the residue is purified on silica gel (eluent: methylene chloride / methanol = 3: 1 to 0: 1). Yield: 0.9 g (32% of theory), Melting point: 250 ° C (decomposition) R _f value: 0.64 (silica gel; methylene chloride / methanol / glacial acetic acid = 3: 1: 0.1) Calculated value xH ₂ OxHCl: C 52.87 H 5.18 N 13.70 Cl
8.67 Found: 53.07 5.02 13.81
8.80

Similarly, the following compounds are obtained. (1) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -carbonylamino] -benzimidazole Melting point: higher than 200 ° C. R _f value: 0.11 (silica gel; ethyl acetate / ethanol =
7: 3) (2) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (3) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Methyl-benzimidazole (4) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Methyl-benzimidazole Ethanolic hydrochloric acid is used. (5) 2- (4-amidino-phenyl) -5 (6)-
[(3-Methoxycarbonyl-propyl) -carbonylamino] -benzimidazole (6) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Methyl-benzimidazole (7) 2- (4-amidino-phenyl) -5-[(3-methoxycarbonyl-propyl) -carbonyl] -1-methyl-benzimidazole (8) 2- (4-amidino-phenyl ) -5-[(4-Methoxycarbonyl-butyl) -carbonyl] -1-methyl-benzimidazole (9) 2- (4-amidino-phenyl) -5 (6)-(2
-Methoxycarbonyl-ethyl-thio) -benzimidazole

(10) 2- (4-amidino-phenyl) -5
(6)-(3-Methoxycarbonyl-propyl-thio)
-Benzimidazole (11) 2- (4-amidino-phenyl) -5 (6)-
[(3-Methoxycarbonyl-propyl) -amino]-
Benzimidazole (12) 5 (6)-[N-acetyl-N- (3-methoxycarbonyl-propyl) -amino] -2- (4-amidino-phenyl) -benzimidazole (13) 2- (4-amidino -Phenyl) -5 (6)-
[(3-Methoxycarbonyl-propyl) -oxy]-
Benzimidazole (14) 2- (4-amidino-phenyl) -5 (6)-(4
-Methoxycarbonyl-butyl) -benzimidazole (15) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -aminomethyl] -benzimidazole (16) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -thiomethyl]
-Benzimidazole (17) 2- (4-amidino-phenyl) -5 (6)-(methoxycarbonyl-methylcarbonyl-aminomethyl)
-Benzimidazole (18) 2- (4-amidino-phenyl) -5 (6)-(4
-Methoxycarbonyl-1-buten-1-yl) -benzimidazole (19) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -3
-Methyl-imidazo [4,5-b] pyridine R _f value: 0.
49 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

(20) 2- (4-amidino-phenyl) -6
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -imidazo [4,5-b] pyridine (21) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -amino Carbonyl] -imidazo [1,2-a] pyridine (22) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -3
-Methyl-imidazo [4,5-c] pyridine (23) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -imidazo [4,5-c] pyridazine (24) 2- (4-Amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -imidazo [4,5-b] pyrazine (25) 2- (4-amidino-phenyl) -2-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -9
-Methyl-purine (26) 8- (4-amidino-phenyl) -6-chloro-2
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -9-methyl-purine (27) 8- (4-amidino-phenyl) -6-methoxy-
2-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -9-methyl-purine (28) 8- (4-amidino-phenyl) -6-dimethylamino-2-[(2-methoxycarbonyl-ethyl) -Aminocarbonyl] -9-methyl-purine (29) 8- (4-amidino-phenyl) -6-amino-2
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -9-methyl-purine

(30) 8- (4-amidino-phenyl) -2
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -9-methyl-6-piperidino-purine (31) 8- (4-amidino-phenyl) -2-[(2-methoxycarbonyl-ethyl) -amino Carbonyl] -9
-Methyl-hypoxanthine (32) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -imidazo [1,2-a] pyrimidine (33) 2- (4 -Amidino-phenyl) -5- [N- (2
-Methoxycarbonyl-ethyl) -methylaminocarbonyl] -1-methyl-benzimidazole (34) 2- (4-amidino-phenyl) -7-fluoro-
5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (35) 2- (4-amidino-phenyl) -4-chloro-6
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (36) 2- (4-amidino-phenyl) -4-bromo-6
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (37) 2- (4-amidino-phenyl) -6-hydroxy-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]- 1-Methyl-benzimidazole (38) 2- (4-amidino-phenyl) -6-methoxy-
5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (39) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Methyl-6-propyloxy-benzimidazole

(40) 2- (4-amidino-phenyl) -6
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -4-methyl-benzimidazole (41) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl]- 1
-Methyl-6-methanesulfonylamino-benzimidazole (42) 6-acetylamino-2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzo Imidazole (43) 2- (4-amidino-phenyl) -6-dimethylamino-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (44) 2- (4-amidino) -Phenyl) -1-n-butyl-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (45) 2- (4-amidino-phenyl) -1-n-decyl-5- [ (2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (46) 2- (4-amidino-phenyl) -1-cyclopropyl -5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (47) 2- (4-amidino-phenyl) -1-cyclohexyl-5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl ] -Benzimidazole (48) 2- (4-amidino-phenyl) -1-benzyl-
5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride _Rf value: 0.22 (silica gel; methylene chloride / methanol)
= 7: 3) (49) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Phenyl-propyl) -benzimidazole

(50) 2- (4-amidino-phenyl) -1
-[2- (3,4-dimethoxy-phenyl) -ethyl]
-5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride _Rf value: 0.20 (silica gel; ethyl acetate / ethanol =
7: 3) (51) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-[2- (2-Pyridyl) -ethyl] -benzimidazole (52) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Pyridylmethyl) -benzimidazole _Rf value: 0.60 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (53) 2- (4-amidino-phenyl) -5-[( 2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(4-Pyridylmethyl) -benzimidazole (54) 2- (4-amidino-phenyl) -1- [3- (1
-Imidazolyl) -propyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (55) 2- (4-amidino-phenyl) -1- [2- (4
-Imidazolyl) -ethyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (56) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl)- Aminocarbonyl] -1
-(2-Piperazino-ethyl) -benzimidazole (57) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(2-Piperidino-ethyl) -benzimidazole (58) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Morpholino-propyl) -benzimidazole (59) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Thiomorpholino-propyl) -benzimidazole R _f value: 0.18 (silica gel; methylene chloride / methanol / concentrated ammonia = 8: 2: 0.1)

(60) 2- (4-amidino-phenyl) -1
-(3-Amino-propyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole _Rf value: 0.29 (silica gel; n-butanol / glacial acetic acid /
(Water = 4: 1: 1, after developing 3 times) (61) 2- (4-amidino-phenyl) -1- (2-hydroxy-ethyl) -5-[(2-methoxycarbonyl-
Ethyl) -aminocarbonyl] -benzimidazole (62) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(2-Methoxy-ethyl) -benzimidazole (63) 1-allyl-2- (4-amidino-phenyl) -5
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (64) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Phenyl-benzimidazole (65) 2- (4-amidino-phenyl) -1- (4-chloro-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (66) 2 -(4-Amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(4-Methoxy-phenyl) -benzimidazole (67) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Methyl-phenyl) -benzimidazole (68) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Pyridyl) -benzimidazole (69) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Methylsulfenyl-phenyl) -benzimidazole

(70) 2- (4-amidino-phenyl) -5
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methoxycarbonylmethyl-benzimidazole (71) 2- (4-amidino-phenyl) -1- (2-methoxycarbonyl-ethyl) -5- [ (2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (72) 2- (4-amidino-phenyl) -1- (2-aminocarbonyl-ethyl) -5-[(2-methoxycarbonyl-ethyl) -Aminocarbonyl] -benzimidazole (73) 2- (4-amidino-phenyl) -1- (2-dimethylaminocarbonyl-ethyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (74) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarb Sulfonyl] -1
-(2-Morpholinocarbonyl-ethyl) -benzimidazole (75) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(2-Thiomorpholinocarbonyl-ethyl) -benzimidazole (76) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-[2- (Methoxycarbonylmethyl-aminocarbonyl) -ethyl] -benzimidazole (77) 2- (5-amidino-2-pyridyl) -5-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-1-Methyl-benzimidazole (78) 2- (4-amidino-2-fluoro-phenyl)-
5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (79) 2- (4-amidino-2-chloro-phenyl) -5
(6)-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole

(80) 2- (4-amidino-2-methoxy-
Phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (81) 2- (4-amidino-2-methyl-phenyl) -5
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (82) 2- (4-amidino-phenyl) -5- (2-methoxycarbonyl-1-piperidinyl) -3-methyl -Imidazo [4,5-b] pyridine (83) 2- (4-amidino-phenyl) -5- (4-methoxycarbonylmethyl-1-piperidinyl) -3-methyl-imidazo [4,5-b] pyridine (84) 2- (4-Amidino-phenyl) -5- (4-methoxycarbonyl-cyclohexyl-methylamino) -3
-Methyl-imidazo [4,5-b] pyridine (85) 2- (4-amidino-phenyl) -5-[(4-methoxycarbonyl-ethyl) -aminocarbonyl] -benzoxazole (86) 2- (4 -Amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzothiazole (87) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -amino Carbonyl] -oxazolo [5,4-b] pyridine (88) 2- (4-amidino-phenyl) -5- (N-methoxycarbonylmethyl-methylamino-carbonylmethyl) -5H-imidazo [4,5-c ] Pyridin-4-one (89) 8- (4-amidino-phenyl) -1- (N-methoxycarbonylmethyl-methylamino-carbonylmethyl) -hypoxanthy The

(90) 8- (4-amidino-phenyl) -1
-(N-Methoxycarbonylmethyl-methylamino-carbonylmethyl) -xanthine (91) 2- (4-amidino-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -3
-Methyl-imidazo [1,2-a] pyridine (92) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(2-Pyrrolidino-ethyl) -benzimidazole (93) 2- (4-amidino-phenyl) -1-methyl-5
-[[2- (5-Tetrazolyl) -ethyl] -aminocarbonyl] -benzimidazole (94) 2- (4-amidino-phenyl) -1-methyl-5
-[(2-phosphono-ethyl) -aminocarbonyl]-
Benzimidazole (95) 2- (4-amidino-phenyl) -1-methyl-5
-[[2- (O-Methyl-phosphono) -ethyl] -aminocarbonyl] -benzimidazole (96) 2- (4-amidino-phenyl) -1-methyl-5
-[(2-Sulfo-ethyl) -aminocarbonyl] -benzimidazole (97) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Methylsulfenyl-propyl) -benzimidazole (98) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-Propargyl-benzimidazole (99) 2- (4-amidino-phenyl) -6- [N-methanesulfonyl-N- (3-methoxycarbonyl-propyl) -amino] -3-methyl-imidazo [4,5- b]
Pyridine

(100) 2- (4-amidino-phenyl)-
5-[(2-Methoxycarbonyl-ethyl) -aminosulfonyl] -1-methyl-benzimidazole (101) 2- (4-amidino-phenyl) -5- (methoxycarbonylmethyl-aminosulfonyl) -1-methyl- Benzimidazole (102) 2- (4-amidino-phenyl) -5- [N-
(4-Methoxycarbonyl-cyclohexyl) -methyl-methylamino] -3-methyl-imidazo [4,5-
b] Pyridine (103) 2- (4-amidino-phenyl) -5- (4-methoxycarbonylmethyl-1-piperazinyl) -3-methyl-imidazo [4,5-b] pyridine (104) 2- (4 -Amidino-phenyl) -5- (4-methoxycarbonylmethyl-3-oxo-1-piperazinyl) -3-methyl-imidazo [4,5-b] pyridine (105) 5-[(2-methoxycarbonyl-ethyl ) -Aminocarbonyl] -1-methyl-2- (4-methylamidino-phenyl) -benzimidazole A concentrated aqueous methylamine solution is used. (106) 2- (n-butylamidino-phenyl) -5-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole n-butylamine is used. (107) 2- (4-amidino-phenyl) -5-[(4-
Methoxycarbonyl-cyclohexyl) -amino] -3
-Methyl-imidazo [4,5-b] pyridine (108) 2- (4-amidino-phenyl) -5- [N-
(2-Methoxycarbonyl-ethyl) -methylaminosulfonyl] -1-methyl-benzimidazole (109) 8- (4-amidino-phenyl) -1- (N-methoxycarbonylmethyl-methylaminocarbonylmethyl) -3- Methyl-xanthine

(110) 2- (4-amidino-phenyl)-
1- (6-amino-hexyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (111) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -sulfonyl]
-Benzimidazole (112) 2- (4-amidino-phenyl) -5 (6)-
[(3-Methoxycarbonyl-propyl) -sulfonyl] -benzimidazole (113) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -sulfonylmethyl] -benzimidazole (114) 2- (4-amidino-phenyl) -1- [3-
(S, S-dioxide-thiomorpholino) -propyl]
-5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (115) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1- (3-methylsulfonyl-phenyl) -benzimidazole (116) 2- (4-amidino-phenyl) -1- [2-
(S, S-dioxide-thiomorpholinocarbonyl)-
Ethyl] -5-[(2-methoxycarbonyl-ethyl)
-Aminocarbonyl] -benzimidazole (117) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1- (3-methylsulfonyl-propyl) -benzimidazole (118) 2- (4-amidino-phenyl) -1- [2-
(4-Benzyl-piperazino) -ethyl] -5-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-Benzimidazole R _f value: 0.49 (silica gel; methylene chloride / methanol
= 8: 2) (119) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1-n-tetradecyl-benzimidazole R _f value: 0.04 (silica gel; ethyl acetate / ethanol =
8: 2)

(120) 2- (4-amidino-phenyl)-
5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1- (3-methoxycarbonyl-propyl) -benzimidazole hydrochloride _Rf value: 0.45 (silica gel; methylene chloride / methanol)
= 8: 2) (121) of 2- (4-amidino-phenyl) -1- (3-carboxy-propyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (120) Obtained as a by-product. R _f value: 0.19 (silica gel; methylene chloride / methanol
= 8: 2) (122) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1- (4-phenyl-butyl) -benzimidazole Melting point: 184-186 ° C _Rf value: 0.13 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (123) 2- (4-amidino -Phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1-Methyl-6-methylamino-benzimidazole hydrochloride-hydrogen acetate Melting point: 260 to 268 ° C (decomposition) _Rf value: 0.24 (silica gel; methylene chloride / methanol / concentrated ammonia = 8: 2: 0.1)

(124) 2- (4-amidino-phenyl)-
5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -6- (N-methoxycarbonylmethyl-methylamino) -1-methyl-benzimidazole hydrochloride _Rf value: 0.42 (silica gel; methylene chloride / methanol / Concentrated ammonia = 5: 2: 0.2) (125) 2- (4-amidino-phenyl) -1- [2-
(4-Amino-3,5-dibromo-phenyl) -ethyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole Melting point: 185 ° C (sintered from 165 ° C) R _f value: 0.43 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (126) 2- (4-amidino-phenyl) -1- (3,3
-Diphenyl-propyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole Melting point: higher than 200 ° C R _f value: 0.11 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6) : 4) (127) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-2-methylpropyl) -aminocarbonyl] -1-methyl-benzimidazole (128) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-propyl) -aminocarbonyl]
-1-Methyl-benzimidazole (129) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-4-phenyl-butyl) -aminocarbonyl] -1-methyl-benzimidazole (130) 2- (4-amidino-phenyl) -6- (N-isobutyloxycarbonyl-N-methyl-amino) -5
-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole Melting point: 104-106 [deg.] C. (decomposition) _Rf value: 0.76 (silica gel; methylene chloride / methanol / concentrated ammonia = 3: 1: 0.1)

(131) 8- (4-amidino-phenyl)-
2-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -7-methyl-purine (132) 8- (4-amidino-phenyl) -6-methoxy-2-[(2-methoxycarbonyl-ethyl)- Aminocarbonyl] -7-methyl-purine (133) 8- (4-amidino-phenyl) -6-dimethylamino-2-[(2-methoxycarbonyl-ethyl)-
Aminocarbonyl] -7-methyl-purine (134) 8- (4-amidino-phenyl) -6-amino-
2-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -7-methyl-purine (135) 8- (4-amidino-phenyl) -2-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
7-Methyl-6-piperidino-purine (136) 8- (4-amidino-phenyl) -2-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
7-Methyl-hypoxanthine (137) 2- (4-amidino-phenyl) -7-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
Imidazo [1,2-a] pyridine (138) 2- (4-amidino-phenyl) -7-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
Imidazo [1,2-a] pyrimidine (139) 2- (4-amidino-phenyl) -7-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
Imidazo [1,2-c] pyrimidine

(140) 2- (4-amidino-phenyl)-
5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzothiazole (141) 8- (4-amidino-phenyl) -3,9-dimethyl-1- (4-methoxycarbonyl-butyl) -xanthine hydrochloride Salt-hydroacetate Melting point: 224 to 226 ° C (decomposition) R _f value: 0.58 (silica gel; n-butanol / glacial acetic acid /
Water = 4: 1: 1.5) (142) 2- (4-amidino-phenyl) -7-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
3-Methyl-imidazo [1,2-a] pyridine (143) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1-methyl-6- (3-phenyl-propyloxy)-
Benzimidazole (144) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1- (4-methyl-benzyl) -benzimidazole (145) 2- (4-amidino-phenyl) -1- [2-
(3,5-Dichloro-4-hydroxy-phenyl) -ethyl] -5-[(2-methoxycarbonyl-ethyl)-
Aminocarbonyl] -benzimidazole (146) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
1-[(2-phenyl-ethyl) -aminocarbonylmethyl] -benzimidazole (147) 2- (4-amidino-phenyl) -5-[(3-
Methoxycarbonyl-piperidino) -carbonyl] -1
-Methyl-benzimidazole _Rf value: 0.61 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (148) 2- (4-amidino-phenyl) -5-[(3-
Methoxycarbonyl-pyrrolidino) -carbonyl] -1
-Methyl-benzimidazole (149) 2- (4-amidino-phenyl) -5-[(2-
Methoxycarbonyl-pyrrolidino) -carbonyl] -1
-Methyl-benzimidazole R _f value: 0.26 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

[0155] Example 4 2- (4-cyano-phenyl) - 5 (6) - [(2-methoxycarbonyl - an ethyl) - carbonylamino] - base
To a mixture of 1.5 g of benzimidazole 5 (6) -amino-2- (4-cyano-phenyl) -benzimidazole, 0.84 g of N-ethyl-diisopropylamine, 20 ml of methylene chloride and 0.05 g of 4-dimethylamino-pyridine. 0.98 g of methyl succinate chloride is added dropwise. The mixture is left at ambient temperature for 16 hours, then slightly acidified water containing a very small amount of methanol is added to it. The crystals obtained are taken up in a mixture of ethyl acetate, tetrahydrofuran and methanol, stirred with 0.1 N hydrochloric acid, the organic solvent is distilled off under reduced pressure and the precipitate obtained is filtered off. Yield: 1.4g (63% of theory), Melting point: 154-156 ° C

Example 5 2- (4-Amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
[3- (S- oxide - thiomorpholino) - propyl]
-Benzimidazole hydrochloride 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
2.2 g of (3-thiomorpholino) -propyl] -benzimidazole hydrochloride are dissolved in 45 ml of glacial acetic acid and dissolved in 5 ml of glacial acetic acid.
0.39 ml of 30% hydrogen peroxide solution is added to it while cooling with ice water. The mixture is stirred for 4 hours with ice cooling, for 16 hours at ambient temperature, the solvent is evaporated off under reduced pressure and the residue is purified by column chromatography (silica gel; methylene chloride / methanol / water = 1: 1: 0
~ 1: 1: 0.1). Yield: 0.6 g (26% of theory), R _f value: 0.46 (silica gel; methylene chloride / methanol / concentrated ammonia = 1: 1: 0.1)

Similarly, the following compounds are obtained. (1) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -sulfinyl] -benzimidazole (2) 2- (4-amidino-phenyl) -5 (6)-
[(3-Methoxycarbonyl-propyl) -sulfinyl] -benzimidazole (3) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -sulfinylmethyl] -benzimidazole (4) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Methylsulfinyl-phenyl) -benzimidazole (5) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-(3-Methylsulfinyl-propyl) -benzimidazole (6) 2- (4-amidino-phenyl) -1- [3-
(S, S-dioxide-thiomorpholino) -propyl]
-5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride The treatment is carried out with 10 volumes of hydrogen peroxide while heating to 50 ° C for 7 hours. R _f value: 0.26 (silica gel; butanol / glacial acetic acid / water =
4: 1: 2, after developing twice) (7) 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1
-[2- (S-oxide-thiomorpholinocarbonyl)
-Ethyl] -benzimidazole

[0158] Example 6 2- (4-aminomethyl-phenyl) - 1 - (3-amino - propyl) -5 - [(2-methoxycarbonyl - ethyl) - aminocarbonyl] - benzo imidazole 1- ( 3-Amino-propyl) -2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl)
3 g of -aminocarbonyl] -benzimidazole are treated with 5 bar of hydrogen for 20 hours at ambient temperature in the presence of 1 g of 10% palladium / charcoal in a mixture of 50 ml of methanol and 10 ml of methanolic hydrochloric acid. After filtering off the catalyst, the mixture is evaporated to dryness under reduced pressure and the residue is purified by chromatography on silica gel (eluent: methanol / 2N ammonia = 5: 1.5 to 5: 2). Yield: 1.5 g (55% of theory), R _f value: 0.24 (silica gel; methanol / 2N ammonia = 5: 1.5, after developing twice)

Similarly, the following compounds are obtained. (1) 2- (4-aminomethyl-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride (2) 2- (4-aminomethyl-phenyl) -5-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-1- (3-thiomorpholino-propyl) -benzimidazole _Rf value: 0.40 (silica gel; methylene chloride / methanol / concentrated ammonia = 8: 2: 0.1) (3) 2- (4-aminomethyl-phenyl)- 5-[(3
-Methoxycarbonyl-propyl) -aminocarbonyl] -1-methyl-benzimidazole (4) 2- (4-aminomethyl-phenyl) -5-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-1-Methyl-benzimidazole dihydrochloride Melting point: Sintered from 185 ° C. R _f value: 0.57 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (5) 2- (4-aminomethyl) -Phenyl) -6-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-Imidazo [4,5-b] pyridine (6) 2- (4-aminomethyl-phenyl) -1- [2-
(3,4-Dimethoxy-phenyl) -ethyl] -5-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole dihydrochloride _Rf value: 0.03 (silica gel; ethyl acetate / ethanol /
Concentrated ammonia = 8: 2: 0.02) (7) 2- (4-aminomethyl-phenyl) -5-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-1-n-tetradecyl-benzimidazole dihydrochloride _Rf value: 0.03 (silica gel; ethyl acetate / ethanol /
Concentrated ammonia = 50: 2: 0.02)

Example 7 2- (4-Aminomethyl-cyclohexyl) -5-
[(2-carboxy - ethyl Le) - aminocarbonyl] -
1-Methyl-benzimidazole 5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-2- (4-phthalimidomethyl-cyclohexyl) -benzimidazole at ambient temperature
It was prepared by treating with a 40% aqueous solution of methylamine for 20 hours. Similarly, the following compound is obtained. (1) 2- [4- (2-amino-ethyl) -phenyl]-
5-[(3-carboxy-propyl) -carbonyl]-
1-Methyl-benzimidazole (2) 2- [4- (2-amino-ethyl) -phenyl]-
5-[(2-carboxy-ethyl) -carbonyl] -1
-Methyl-benzimidazole (3) 2- (4-amino-cyclohexyl) -5-[(2
-Carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole

Example 8 2- (4-Aminomethyl-cyclohexyl) -5-
[(2-methoxy-carbonylation Le - ethyl) - Aminokarubo
Nyl] -1-methyl-benzimidazole dihydrochloride 2- (4-aminomethyl-cyclohexyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
Prepared from 1-methyl-benzimidazole by treatment with saturated methanolic hydrochloric acid at ambient temperature. Similarly, the following compound is obtained. (1) 2- [4- (2-amino-ethyl) -phenyl]-
5-[(3-Methoxycarbonyl-propyl) -carbonyl] -1-methyl-benzimidazole dihydrochloride (2) 2- [4- (2-amino-ethyl) -phenyl]-
5-[(2-Methoxycarbonyl-ethyl) -carbonyl] -1-methyl-benzimidazole dihydrochloride (3) 5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-2- ( 4-Methylaminomethyl-phenyl) -benzimidazole dihydrochloride (4) 2- (4-amino-cyclohexyl) -5-[(2
-Methoxycarbonyl-ethyl) -aminocarbonyl]
-1-methyl-benzimidazole dihydrochloride

[0162] Example 9 5 - [(2-methoxycarbonyl - ethyl) - aminocarbonyl] -1-methylcarbamoyl-2-(4-methylamino-methylcarbamoyl
L-phenyl) -benzimidazole 5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-2- [4- (N-trifluoroacetyl-methylaminomethyl) -phenyl] -benzimidazole, Prepared by treatment with 2N sodium hydroxide solution. Example 10 2- (1-amidino-4-piperidinyl) -5-[(2
-Methoxycarbonyl- ethyl) -aminocarbonyl]
-1-Methyl-benzimidazole 5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-2- (4-piperidinyl)-
Prepared from benzimidazole and S-ethylisothiourea hydrobromide by heating to 100 ° C for 4 hours in dimethylformamide in the presence of sodium carbonate.
Similarly, the following compound is obtained. (1) 2- (4-guanidinomethyl-phenyl) -5-
[(2-Methoxycarbonyl-ethyl) -carbonyl]
-1-Methyl-benzimidazole (2) 2- (4-amidino-1-piperazinyl) -5-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole

[0163] Example 11 2- (3-guanidino - phenyl) -5 - [(3-methoxycarbonyl - propyl) - aminocarbonyl] -1
-Methyl-benzimidazole 2- (3-amino-phenyl) -5-[(3-methoxycarbonyl-propyl) -aminocarbonyl] -1-methyl-benzimidazole hydrochloride from dioxane at reflux with cyanamide for 3 hours. It was prepared by

Example 12 2- (4-Methoxycarbonylamidino-phenyl)-
5-[(2- methoxycarbonyl-ethyl) -aminoca
Rubonyl] -1-methyl-benzimidazole 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1 -methyl-benzimidazole hydrochloride (0.26 g) in methylene chloride
Suspend in 50 ml, cool with ice, 0.5 ml N-ethyl-diisopropylamine and methyl chloroformate 0.
Add 067 ml. The mixture is stirred at ambient temperature, 0.
After 5 hours, N-ethyl-diisopropylamine was added to 0.5
ml and 0.03 ml of methyl chloroformate are added, and after 0.5 hours another 0.1 ml of N-ethyl-diisopropylamine and 0.03 ml of methyl chloroformate are added. The mixture is stirred for a further 0.5 h, evaporated under reduced pressure and purified by column chromatography (silica gel; eluent:
Ethyl acetate / ethanol = 100: 2.5 to 100: 12.5). Yield: 0.12 g (40% of theory), R _f value: 0.41 (silica gel; ethyl acetate / ethanol =)
8: 2) Similarly, the following compound is obtained. (1) 2- (4-isobutyloxycarbonylamidino-
Phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (2) 5-[(2-ethoxycarbonyl-ethyl) -aminocarbonyl] -2- (4-methoxy Carbonylamidino-phenyl) -1-methyl-benzimidazole (3) 5-[(2-isobutyloxycarbonyl-ethyl) -aminocarbonyl] -2- (4-methoxycarbonylamidino-phenyl) -1- (4-phenyl -Butyl) -benzimidazole (4) 2- (4-acetoxymethyloxycarbonylamidino-phenyl) -5-[(2-methoxycarbonyl-
Ethyl) -aminocarbonyl] -1- (4-phenyl-
Butyl) -benzimidazole (5) 2- (4-cyano-phenyl) -6- (N-isobutyloxycarbonyl-N-methyl-amino) -5-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole R _f value: 0.63 (silica gel; methylene chloride / methanol / glacial acetic acid = 25: 1: 0.1)

Example 13 2- (4-amidino-phenyl) -1- [2- (3,4
- dimethoxy - phenyl) - ethyl] -5 - [(2-isopropyl-oxycarbonyl - ethyl) - amino Nokarubo
Nyl] -benzimidazole dihydrochloride 2- (4-amidino-phenyl) -1- [2- (3,4
0.6 g of -dimethoxy-phenyl) -ethyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride was added to 50 ml of ice-cold saturated isopropanolic hydrochloric acid and petroleum ether was added to the top. Pour and carefully stir until most of the solid product goes into solution. The mixture is left at ambient temperature for 16 hours, the precipitate is filtered off, the filtrate is evaporated under reduced pressure and the residue is stirred with tetrahydrofuran. Yield: 0.5 g (76% of theory), Melting point: 210 ° C (sintered from 180 ° C)

Similarly, the following compounds are obtained. (1) 2- (4-amidino-phenyl) -5-[(2-n
-Butyloxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole dihydrochloride (2) 2- (4-amidino-phenyl) -5-[(2-isopropyloxycarbonyl-ethyl) -aminocarbonyl] -1- (4-phenyl-butyl) -benzimidazole dihydrochloride (3) 2- (4-amidino-phenyl) -5-[(2-cyclohexyloxycarbonyl-ethyl) -aminocarbonyl] -1- (4 -Phenyl-butyl) -benzimidazole dihydrochloride _Rf value: 0.69 (silica gel; n-butanol / glacial acetic acid /
Water = 3: 1: 1) (4) 2- (4-amidino-phenyl) -5-[(2-n
-Hexyloxycarbonyl-ethyl) -aminocarbonyl] -1- (4-phenyl-butyl) -benzimidazole dihydrochloride (5) 2- (4-amidino-phenyl) -5-[(2-isobutyloxycarbonyl- Ethyl) -aminocarbonyl] -1- (4-phenyl-butyl) -benzimidazole dihydrochloride

(6) 2- (4-amidino-phenyl) -5
-[(2-Cyclohexylmethyloxycarbonyl-ethyl) -aminocarbonyl] -1- (4-phenyl-butyl) -benzimidazole dihydrochloride _Rf value: 0.67 (silica gel; n-butanol / glacial acetic acid /
Water = 3: 1: 1) (7) 2- (4-amidino-phenyl) -5-[[2-
(2-Indanyloxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole dihydrochloride The corresponding carboxylic acid is used as the starting material and heated in the presence of hydrogen chloride. (8) 2- (4-amidino-phenyl) -1-methyl-5
Use the same procedure as for [[2-[(1-naphthyl) -methyloxycarbonyl] -ethyl] -aminocarbonyl] -benzimidazole dihydrochloride (7). (9) 2- (4-Amidino-phenyl) -5-[(2-cinnamyloxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole dihydrochloride The same procedure is used as for (7).

(10) 2- (4-amidino-phenyl) -1
-Methyl-5-[[2-[(2-norbornyl) -methyloxycarbonyl] -ethyl] -aminocarbonyl]
-Benzimidazole dihydrochloride _Rf value: 0.75 (silica gel; dichloromethane / methanol = 2: 1) (11) 2- (4-amidino-phenyl) -1-methyl-5
-[[2- (2-norbornyloxy-carbonyl)-
Use the same procedure as for ethyl] -aminocarbonyl] -benzimidazole dihydrochloride (7). (12) 2- (4-amidino-phenyl) -1-methyl-5
The same procedure is used as for-[[2-[(5-phenyl-butyl) -oxycarbonyl] -ethyl] -aminocarbonyl] -benzimidazole dihydrochloride (7). (13) 2- (4-amidino-phenyl) -1-methyl-5
The same procedure is used as for [[2-[(4-phenyl-butyl) -oxycarbonyl] -ethyl] -aminocarbonyl] -benzimidazole dihydrochloride (7). (14) 2- (4-amidino-phenyl) -5-[(2-cyclooctyloxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole dihydrochloride _Rf value: 0.67 (silica gel; n- Butanol / glacial acetic acid /
Water = 3: 1: 1)

(15) 2- (4-amidino-phenyl) -1
-(4-Phenyl-butyl) -5-[[2-[(2-phenyl-ethyl) -oxycarbonyl] -aminocarbonyl] -benzimidazole dihydrochloride _Rf value: 0.78 (silica gel; n-butanol / ice) Acetic acid /
Water = 3: 1: 1) (16) 2- (4-amidino-phenyl) -1- [2- (4
-Amino-3,5-dibromo-phenyl) -ethyl]-
5-[(2-isopropyloxycarbonyl-ethyl)
-Aminocarbonyl] -benzimidazole dihydrochloride _Rf value: 0.18 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (17) 2- (4-amidino-phenyl) -1- [2 -(2
-Bromo-4,5-dimethoxy-phenyl) -ethyl]
-5-[[2- (2-norbornyloxycarbonyl)
-Ethyl] -aminocarbonyl] -benzimidazole-dihydroacetate 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2-
The (3,4-dimethoxy-phenyl) -ethyl] -benzimidazole dihydrobromide salt is heated with thionyl chloride for 2 hours and the resulting acid chloride is converted with norborneol to the corresponding ester. Purification is carried out by chromatography on silica gel (eluent: n-butanol /
Glacial acetic acid / water = 3: 1: 1) (18) 2- (4-amidino-phenyl) -1- [2- (2
-Bromo-4,5-dimethoxy-phenyl) -ethyl]
-5-[[2- (2-indanyloxycarbonyl)-
Ethyl] -aminocarbonyl] -benzimidazole-
Use the same procedure as for dihydroacetate (17). R _f value: 0.65 (silica gel; n-butanol / glacial acetic acid /
Water = 3: 1: 1)

Example 14 2-[(4-Cyano-phenyl) -oxymethyl] -5
(6) - Etokishikaru Boniru - methoxy - Benzoimida
Tetrazole Ethyl 3-amino-4 - [(4-cyano-phenyl) - -
4.5 g of oxymethylcarbonylamino] -phenoxy-acetate are melted and kept at 200 ° C. for 15 minutes. The product was purified by silica gel (eluent: methylene chloride / methanol / concentrated ammonia = 30: 1: 0.1), then neutral aluminum oxide (eluent: methylene chloride / methanol = 100: 1).
Purify by column chromatography on and crystallize with a 1: 2 mixture of methylene chloride and ether. Yield: 2.5 g (58% of theory), melting point: 111-112 ° C R _f value: 0.22 (silica gel; methylene chloride / methanol / concentrated ammonia = 30: 1: 0.1)

Similarly, the following compounds are obtained. (1) 1- [2- (4-Benzyl-piperazino) -ethyl] -2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole _Rf value : 0.58 (silica gel; methylene chloride / methanol / concentrated ammonia = 19: 1: 0.1, after developing 3 times) (2) 1- (3-amino-propyl) -2- (4-cyano-phenyl) -5- [(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride 3-amino-4- (3-amino-propylamino) -benzoic acid- [N- (2-methoxycarbonyl-ethyl)-
The amido] hydrochloride-hydrogen acetate is acylated by first treating it with 4-cyano-benzoyl chloride in chlorobenzene at a bath temperature of 140 ° C., while distilling off the chlorobenzene. The residue is heated to 190 ° C for 10 minutes. Melting point: 252 ° C. (decomposition, sintering from 115 ° C.) R _f value: 0.54 (silica gel; methylene chloride / methanol / concentrated ammonia = 9: 1: 0.2, after developing twice) (3) 2- (4-cyano -Phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
Methyl-6-methylamino-benzimidazole Heat for 35 minutes. Melting point: 203-205 ° C. R _f value: 0.68 (silica gel; methylene chloride / methanol / concentrated ammonia = 30: 1: 0.1, after 3 times development) (4) 8- (4-cyano-phenyl) -3,9 -Dimethyl-xanthine 5-amino-3-methyl-4-methylamino-pyrimidine-2,6-dione is acylated with 4-cyano-benzoyl chloride in tetrahydrofuran in the presence of 4-dimethylamino-pyridine and the evaporation residue 45 to 200-205 ℃
Heated for minutes. R _f value: 0.79 (silica gel; methylene chloride / methanol / glacial acetic acid = 9: 1: 0.1, after developing twice)

Example 15 2- (4-Amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl ] -1- (2-piperazino-ethyl) -benzimidazole-hydrogenacetate
Doo 2- (4-amidino-phenyl) - 1- [2- (4-benzyl - piperazino - ethyl] -5 - [(2-carboxy - ethyl) - aminocarbonyl] - glacial acetic acid 100 ml benzimidazole 0.30g Dissolved in 1.8 g of palladium oxide
For 36 hours at ambient temperature in the presence of 5 bar hydrogen. After filtering off the catalyst, the filtrate is evaporated under reduced pressure and the residue is digested with acetone then ether. Yield: 0.27 g (92% of theory), Melting point: 80 ° C (decomposition) R _f value: 0.14 (silica gel; isopropanol / water / concentrated ammonia = 7: 2: 1, after developing twice)

Similarly, the following compounds are obtained. (1) 2- (4-amidino-phenyl) -5 (6)-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole hydrochloride The treatment is carried out in methanol with 10% palladium / charcoal. R _f value: 0.65 (silica gel; methylene chloride / methanol
= 3: 1) (2) 2- (4-amidino-phenyl) -1- (4-phenyl-butyl) -5-[(2-pivaloyloxymethyloxycarbonyl-ethyl) -aminocarbonyl] -benzo Imidazole (3) 2- (4-amidino-phenyl) -5-[[2-
[(1-Ethoxycarbonyloxy-ethyl) -oxycarbonyl] -ethyl] -aminocarbonyl] -1-
(4-Phenyl-butyl) -benzimidazole (4) 2- (4-amidino-phenyl) -5-[(2-cyclohexyloxycarbonyloxy-methyloxycarbonyl-ethyl) -aminocarbonyl] -1- (4-
Phenyl-butyl) -benzimidazole (5) 5-[(2-acetoxymethyloxycarbonyl-
Ethyl) -aminocarbonyl] -2- (4-amidino-
Phenyl) -1- (4-phenyl-butyl) -benzimidazole

(6) 2- (4-amidino-phenyl) -5
-[(1,2-Bis-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole (7) 2- (4-amidino-phenyl) -5-[[2-carboxy-1-[(1 -Carboxy-2-phenyl-ethyl) -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole (8) 2- (4-amidino-phenyl) -5-[[2-carboxy-1- [(1-Carboxy-2-methyl-propyl) -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole (9) 2- (4-amidino-phenyl) -5-[[2-carboxy -1-[(1-Carboxy-2- (4-hydroxy-phenyl) -ethyl) -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimi Zole (10) 2- (4-amidino-phenyl) -5-[[2-carboxy-1-[[1-carboxy-2- (4-methoxy-phenyl) -ethyl) -aminocarbonyl] -ethyl]- Aminocarbonyl] -1-methyl-benzimidazole (11) 2- (4-amidino-phenyl) -5-[[2-carboxy-1-[[2- (4-methoxy-phenyl)-
Ethyl) -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole

Example 16 2- (4-Cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1- (3
- thiomorpholino - propyl) - Benzoimida tetrazole 3-amino-4- (3-thiomorpholino - propylamino) - benzoic acid - [N-(2-methoxycarbonyl - ethyl) - amide] while heating the hydrochloride salt 48.6g Glacial acetic acid 50
Dissolve in 0 ml, 19.5 g of 4-cyano-benzoyl chloride
And heating the mixture on a steam bath for 1 hour,
Heat for a further 2 hours at a bath temperature of 120 ° C. The mixture is evaporated under reduced pressure and the residue is purified by chromatography on silica gel (eluent: methylene chloride / methanol / concentrated ammonia = 9: 1: 0 to 8: 2: 0.2). Yield: 33.7 g (58% of theory), R _f value: 0.84 (silica gel; methylene chloride / methanol / concentrated ammonia = 19: 1: 0.1, after developing 3 times)

Similarly, the following compounds are obtained. (1) 2- (4-cyano-phenyl) -1- [2- (3,
4-dimethoxy-phenyl) -ethyl] -5-[(2-
Methoxycarbonyl-ethyl) -aminocarbonyl]-
Acylation with benzimidazole 4-cyano-benzoyl chloride is first carried out in methylene chloride with the addition of N-ethyl-diisopropylamine. After evaporating off the solvent, the residue is taken up in glacial acetic acid and heated to 100 ° C for 1.5 hours. R _f value: 0.36 (silica gel; ethyl acetate / ethanol /
Concentrated ammonia = 50: 2: 0.1) (2) 2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
Use the same procedure as (3-pyridylmethyl) -benzimidazole (1) and heat in glacial acetic acid for 3 hours. R _f value: 0.40 (silica gel; ethyl acetate / ethanol =
8: 2) (3) 2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
The same procedure is used as for n-tetradecyl-benzimidazole (1). R _f value: 0.60 (silica gel; ethyl acetate / ethanol /
Concentrated ammonia = 50: 2: 0.02) (4) 2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
(3-Methoxycarbonyl-propyl) -benzimidazole Use the same procedure as (1) with triethylamine as auxiliary base. A 3: 1 mixture of tetrahydrofuran and methylene chloride is used as the solvent. R _f value: 0.68 (silica gel; methylene chloride / methanol
= 37: 3)

(5) 1-benzyl-2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl)
-Aminocarbonyl] -benzimidazole (4) The same procedure is used. R _f value: 0.77 (silica gel; methylene chloride / methanol
= 9: 1) (6) 2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-
The same procedure is used as (4-phenyl-butyl) -benzimidazole (1). R _f value: 0.61 (silica gel; ethyl acetate / ethanol = 5
0: 2) (7) 1- [2- (4-amino-3,5-dibromo-phenyl) -ethyl] -2- (4-cyano-phenyl) -5
Use the same procedure as-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (1). Melting point: 168 to 170 ° C., R _f value: 0.66 (silica gel; ethyl acetate / ethanol =
8: 2) (8) 2- (4-Cyano-phenyl) -1- (3,3-diphenyl-propyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole Melting point: 157 ~ 159 ° C, R _f value: 0.65 (silica gel; ethyl acetate / ethanol =
9: 1) (9) Use the same procedure as 2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-pyrrolidino) -carbonyl] -1-methyl-benzimidazole (1). Melting point: 174 to 176 ° C., R _f value: 0.36 (silica gel; ethyl acetate / ethanol =
9: 1) (10) 2- (4-Cyano-phenyl) -5-[(3-methoxycarbonyl-piperidino) -carbonyl] -1-methyl-benzimidazole Use the same procedure as (1). Melting point: 185 to 186 ° C., R _f value: 0.43 (silica gel; ethyl acetate / ethanol =
9: 1) (11) 2- (4-cyano-phenyl) -6-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -3-
The same procedure is used as for methyl-imidazo [4,5-b] pyridine (1). Melting point: 195-197 ° C., R _f value: 0.51 (silica gel; ethyl acetate / ethanol =
9: 1)

Example 17 2- (4-Aminomethyl-phenyl) -1- (3-amino-propyl) -5-[(2-carboxy-ethyl)-
Aminocarbonyl] - benzimidazole - hydrogen Asete
Over preparative 2- (4-aminomethyl-phenyl) - 1 - (3-amino - propyl) -5 - [(2-methoxycarbonyl - ethyl) - aminocarbonyl] - benzimidazole 0.8g
Is left in 10 ml of 48% hydrobromic acid at ambient temperature for 20 hours. The mixture is concentrated by evaporation under reduced pressure and the residue is purified by chromatography on silica gel (eluent: n-butanol / glacial acetic acid / water = 4: 1: 1 to 4: 2: 2). Yield: 0.6 g (67% of theory), R _f value: 0.66 (reverse phase plate RP18; methanol / 5% sodium chloride solution / concentrated hydrobromic acid = 6: 10: 0.01)

Similarly, the following compounds are obtained. (1) 2- (4-aminomethyl-phenyl) -5-[(2
-Carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole-hydrobromide Melting point: 220
Sintering from C _Rf value: 0.87 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (2) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -Aminocarbonyl] -1- [2-
(3,4-Dimethoxy-phenyl) -ethyl] -benzimidazole-dihydrobromide _Rf value: 0.72 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (3) 2- (4-Amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Pyridylmethyl) -benzimidazole-dihydrobromide _Rf value: 0.73 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (4) 2- (4-aminomethyl-phenyl)- 5-[(2
-Carboxy-ethyl) -aminocarbonyl] -1-n
-Tetradecyl-benzimidazole dihydrobromide _Rf value: 0.05 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (5) 2- (4-aminomethyl-phenyl) -5 -[(2
-Carboxy-ethyl) -aminocarbonyl] -1-
[2- (3,4-dimethoxy-phenyl) -ethyl]-
Benzimidazole-dihydrobromide R _f value: 0.67 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (6) 2- (4-amidino-phenyl) -5-[(2 -Carboxy-ethyl) -aminocarbonyl] -1-n-tetradecyl-benzimidazole-dihydrobromide _Rf value: 0.01 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (7 ) 2- (4-Amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (4-
(Phenyl-butyl) -benzimidazole dihydrobromide _Rf value: 0.08 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4)

(8) 2- (4-amidino-phenyl) -1
-[2- (4-amino-3,5-dibromo-phenyl)
-Ethyl] -5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole-dihydrobromide Melting point: higher than 225 ° C _Rf value: 0.57 (reverse phase plate RP18; methanol / 5% chloride) Sodium solution = 6: 4) (9) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3,
3-diphenyl-propyl) -benzimidazole-dihydrobromide _Rf value: 0.71 (silica gel; n-butanol / glacial acetic acid /
Water = 3: 1: 1) (10) 2- (4-amidino-phenyl) -5-[(3-carboxy-piperidino) -carbonyl] -1-methyl-
Benzimidazole-dihydrobromide _Rf value: 0.49 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (11) 2- (4-amidino-phenyl) -5-[(3 -Carboxy-pyrrolidino) -carbonyl] -1-methyl-
Benzimidazole-dihydrobromide (12) 2- (4-amidino-phenyl) -5-[(2-carboxy-pyrrolidino) -carbonyl] -1-methyl-
Benzimidazole-hydrobromide R _f value: 0.46 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6: 4) (13) 2- (4-amidino-phenyl) -6-[(2 -Carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [4,5-b] pyridine-dihydrobromide _Rf value: 0.74 (reverse phase plate RP18; methanol / 5% sodium chloride solution = 6) :Four)

Example 18 2- (4-Cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyi
First, 3-amino-4-methylamino-benzoic acid- [N -benzimidazole
-(2-Methoxycarbonyl-ethyl) -amide] 4.7 g
Is stirred with 40 ml of phosphorus oxychloride at ambient temperature, then 3.1 g of 4-cyano-benzoyl chloride are added and the mixture is heated to 90 ° C. for 8 hours. The phosphorus oxychloride is distilled off under reduced pressure, the residue is stirred in 500 ml of water at 30 ° C. and sodium hydrogen carbonate is added in several portions to neutralize. The precipitate is suction filtered and extracted with ethyl acetate. The ethyl acetate phase is evaporated down, the residue is combined with the precipitate and purified by chromatography on silica gel (eluent: ethyl acetate /
Ethanol = 100: 1 to 100: 5). The product obtained is boiled with ethyl acetate for final purification. Yield: 1.86 g (27% of theory), R _f value: 0.51 (silica gel; ethyl acetate / ethanol =)
9: 1)

Example 19 2- (4-Cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -6- (N
- methoxycarbonylmethyl -N- methyl - amino) -
1-Methyl-benzimidazole 2- (4-cyano-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-6-methylamino-benzimidazole Dimethylformamide 5.0 g warmed Dissolve in 20 ml and add 2.3 ml N-ethyl-diisopropylamine. 1.2 ml of methyl bromoacetate are added dropwise and the mixture is heated on a steam bath for 5 hours. A further 1.2 ml of N-ethyl-diisopropylamine and 0.6 ml of methyl bromoacetate are added and the mixture is heated for a further 3 hours. After evaporating off the solvent under reduced pressure, it is stirred with 50 ml of water for 2 hours at ambient temperature, suction filtered, the residue is dried and triturated with ethyl acetate. Yield: 3.2g (54% of theory), Melting point: 174-176 ° C _Rf value: 0.34 (silica gel; methylene chloride / methanol)
= 19: 1, after developing 3 times) Similarly, the following compound is obtained. (1) 8- (4-Cyano-phenyl) -3,9-dimethyl-1- (4-ethoxycarbonyl-butyl) -xanthine Dimethyl sulfoxide is used as a solvent, potassium carbonate is used as a base, and the reaction mixture is Heat to 80 ° C. for 4 hours. Melting point: 148 to 150 ° C R _f value: 0.33 (silica gel; ethyl acetate)

[0183] Example 20 2- (4-benzyloxycarbonyl-amidinophenyl - phenyl) -1- (4-phenyl - butyl) -5 - [(2-pivaloyloxymethyl oxycarbonyl - ethyl Le) - A
Minocarbonyl] -benzimidazole 2- (4-benzyloxycarbonylamidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (4-phenyl-butyl) -benzimidazole was added to dimethyl sulfoxide. Prepared by adding potassium iodide in and reacting with pivaloyloxymethyl chloride in the presence of potassium carbonate at ambient temperature. Similarly, the following compound is obtained. (1) 2- (4-benzyloxycarbonylamidino-phenyl) -5-[[2-[(1-ethoxycarbonyloxy-ethyl) -oxycarbonyl] -ethyl] -aminocarbonyl] -1- (4-phenyl -Butyl) -benzimidazole (2) 2- (4-benzyloxycarbonylamidino-phenyl) -5-[(2-cyclohexyloxycarbonyloxymethyloxycarbonyl-ethyl) -aminocarbonyl] -1- (4-phenyl -Butyl) -benzimidazole (3) 5-[(2-acetoxymethyloxycarbonyl-
Ethyl) -aminocarbonyl] -2- (4-benzyloxycarbonylamidino-phenyl) -1- (4-phenyl-butyl) -benzimidazole

Example 21 2- (4-Diethylphosphorylamidino-phenyl)-
5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl ] -1- (4-phenyl-butyl) -benzoyl
Midazole 2- (4-amidino-phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl ] -1-
Prepared by reacting (4-phenyl-butyl) -benzimidazole with diethylphosphoryl cyanide in dimethylformamide.

[0185] Example 22 2- (4-benzyloxycarbonyl-amidinophenyl - phenyl) -5 - [(1,2-Bis - benzyloxycarbonyl - ethyl) - aminocarbonyl] -1-methylation - Ben
2- (1H-benzotriazol-1-yl)-in tetrahydrofuran from 2- imidazole 2- (4-benzyloxycarbonylamidino-phenyl) -1-methyl-benzimidazole-4-carboxylic acid and dibenzyl aspartate
Prepared by adding 1,1,3,3-tetramethyluronium-tetrafluoroborate.

Similarly, the following compounds are obtained. (1) 2- (4-benzyloxycarbonylamidino-phenyl) -5-[[2-benzyloxycarbonyl-1
-[(1-benzyloxycarbonyl-2-phenyl-
Ethyl) -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole (2) 2- (4-benzyloxycarbonylamidino-phenyl) -5-[[2-benzyloxycarbonyl-1
-[(1-Benzyloxycarbonyl-2-methyl-propyl) -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole (3) 2- (4-benzyloxycarbonylamidino-phenyl) -5 -[[2-benzyloxycarbonyl-1
-[[1-Benzyloxycarbonyl-2- (4-benzyloxy-phenyl) -ethyl] -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole (4) 2- (4-benzyloxy Carbonylamidino-phenyl) -5-[[2-benzyloxycarbonyl-1
-[[1-Benzyloxycarbonyl-2- (4-methoxy-phenyl) -ethyl] -aminocarbonyl] -ethyl] -aminocarbonyl] -1-methyl-benzimidazole (5) 5-[[2-benzyloxy Carbonyl-1-
[[2- (4-Methoxy-phenyl) -ethyl] -aminocarbonyl] -ethyl] -aminocarbonyl] -2-
(4-benzyloxycarbonyl-amidino-phenyl) -1-methyl-benzimidazole

[0187] Example 23 2- [4- (1-amino - cyclopropyl) - phenyl] -5 - [(2-methoxycarbonyl - ethyl) - aminocarbonyl] -1-methyl - benzo imidazole 2- [ 4- (1-tert.butyloxycarbonylamino-cyclopropyl) -phenyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole from methylene chloride at ambient temperature. Prepared by treating with trifluoroacetic acid. Similarly, the following compound is obtained. (1) 2- [4- (1-amino-cyclopentyl) -phenyl] -5-[(2-methoxycarbonyl-ethyl)-
Aminocarbonyl] -1-methyl-benzimidazole

[0188] Example 24 2- (1-amino-5-indanyl) -5 - [(2-methoxycarbonyl - an ethyl) - aminocarbonyl] -1
-Methyl -benzimidazole 2- (1-hydroxyimino-5-indanyl) -5-
10% at ambient temperature in a 50: 1 mixture of [(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole to methanol and methanolic hydrochloric acid.
Prepared by reduction with 5 bar hydrogen in the presence of palladium on charcoal. Similarly, the following compound is obtained. (1) 2- (1-amino-1,2,3,4-tetrahydro-6-naphthyl) -5-[(2-methoxycarbonyl-
Ethyl) -aminocarbonyl] -1-methyl-benzimidazole

Example 25 2- [4- (2-amino-2-propyl) -phenyl]
-5 - [(2-methoxycarbonyl - ethyl) - aminocarbonyl] -1-methyl - benzo imidazole 2- [4- (2-amino-2- propyl) -
Prepared from phenyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole by treatment with [bis (trifluoroacetoxy) -iodo] benzene in acetonitrile / water at ambient temperature. did.

Example 26 2- (4-amidino-phenyl) -1-methyl-5-
[[2-[[2- (2-oxo-1-pyrrolidinyl)-
Ethyl] - oxycarbonyl] - ethyl] - amino Nokaru
Bonyl] -benzimidazole 2- (4-amidino-phenyl) -1-methyl-5-
[(2-Carboxyethyl) -aminocarbonyl] -1
Prepared from -methyl-benzimidazole by heating 1- (2-hydroxy-ethyl) -2-pyrrolidone and excess trimethylchlorosilane to 60 ° C for 36 hours. Similarly, the following compound is obtained. (1) 2- (4-amidino-phenyl) -1-methyl-5
-[[2-[(2-Phenyl-ethyl) -oxycarbonyl] -ethyl] -aminocarbonyl] -benzimidazole (2) 2- (4-amidino-phenyl) -1- (4-phenyl-butyl)- 5-[[2-[(3-pyridyl) methyloxycarbonyl] -ethyl] -aminocarbonyl]
-Benzimidazole

Example 27 Dry ampoule composition containing 2.5 mg of active substance per ml Composition: Active substance 2.5 mg Mannitol 50.0 mg Water up to 1.0 ml for injection Preparation: Active substance and mannitol are dissolved in water. After transferring the solution to an ampoule, it is freeze-dried. At the time of use, the solution is replenished with water for injection.

Example 28 Dry ampoule containing 35 mg of active substance per 2 ml Composition: Active substance 35.0 mg Mannitol 100.0 mg Water for injection up to 2.0 ml Preparation: Active substance and mannitol are dissolved in water. After transferring the solution to an ampoule, it is freeze-dried. At the time of use, the solution is replenished with water for injection.

Example 29 Tablets containing 50 mg of active substance Preparation: Mix (1), (2) and (3) together and granulate with the aqueous solution of (4). Mix (5) with dry granules. From this mixture, biplanar, double-sided, single-sided, notched compressed tablets are produced. Tablet diameter: 9 mm.

Example 30 Tablets containing 350 mg of active substance Preparation: Mix (1), (2) and (3) together and granulate with the aqueous solution of (4). Mix (5) with dry granules. From this mixture, bilayer, double-sided, one-sided, notched compressed tablets are produced. Tablet diameter: 12m
m.

Example 31 Capsules containing 50 mg of active substance Preparation: Grind (1) with (3). Add this ground material to the mixture of (2) and (4) and mix well. The powder mixture is packed into size 3 hard gelatin elongated capsules in a capsule filling machine.

Example 32 Capsules containing 350.0 mg of active substance Preparation: Grind (1) with (3). Add this ground material to the mixture of (2) and (4) and mix well. This powder mixture is packed into size 0 hard gelatin elongated capsules in a capsule filling machine.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI Technical indication location C07D 235/18 235/26 235/28 C 235/30 401/04 8829-4C 471/04 104 Z 8829-4C 106 Z 8829-4C 487/04 144 144 7019-4C 498/04 105 8415-4C 513/04 341 8415-4C (72) Inventor Frank Himmelsbach Federal Republic of Germany Wei 7951 Mittel Biberach Ahornweg 16 (72) Inventor Günter Linz Weg 7951 Mittel Bibelach Drosselweg 14 (72) Inventor Thomas Mueller Weg 7950 Bibelach Gymnadium Strasse 16 (72) Inventor Johannes Weisenberger Weg 7950 Bibe Tsu Ha 1 Ha Idun Weserblick click 5 (72) inventor Elk Zewaruto Becker Federal Republic of Germany Weserblick 7950 Bibera' Ha Hugh panel felt Strasse 26

Claims (10)

[Claims] 1. A general formula:5-membered heterocyclic compound represented by
Body, stereoisomers, mixtures thereof and salts thereof.
[In the formula, R₁Is a hydrogen atom, a fluorine atom, a chlorine atom or
Is a bromine atom; an alkyl group, an aralkyl group, an aryl group,
Heteroaryl group, R₃O- group, (R₃)₂N- group, R_FourCO-NR₃
-Group, alkylsulfonyl-NR₃-Group, arylsulfoni
Le-NR₃-Group, R₃S- group, R₃SO-group, R₃SO₂-Group or R
_FiveRepresents a group (in the formula, R₃Is a hydrogen atom, C_1-6Alkyl
Group, aryl group, heteroaryl group, aralkyl group,
Ruboxyalkyl group or alkoxycarbonylalkoxy
Represents a radical, R_FourIs a hydrogen atom; 1 to 6 carbon atoms each
An alkyl group or an alkoxy group having; an aryl group,
1 to 6 carbons in a heteroaryl group or alkyl moiety
R represents an aralkyl group having an elementary atom, and R_FiveIs azechi
Dino group, pyrrolidino group, hexamethyleneimino group
Represents a heptamethyleneimino group or a piperidino group,
The 4-position methylene group is an oxygen atom; sulfenyl group, sulfone
Or a sulfonyl group; or R₃Group, R_FourCO-
Group, alkylsulfonyl or arylsulfonyl group
(In the formula, R₃And R_FourIs as defined above)
May be substituted by an imino group substituted by
I) X is an oxygen atom, a sulfur atom or a nitrogen atom or -N
R₂Represents a group (in the formula, R₂Is a hydrogen atom; straight chain or
Branch C_1-15Alkyl group; straight or branched C_3-10Alkenyl
A group or an alkynyl group (the double or triple bond of which is
Not directly bound to nitrogen atoms);
Cycloalkyl having 3 to 7 carbon atoms in the rukyl moiety
Kill group or cycloalkylalkyl group; aryl group
Or heteroaryl group; C_2-6Alkyl group (this is -NR₂-
R from the β-position to the nitrogen atom of the group ₃O-group, (R₃)₂N-
Base, R_FourCO-NR₃-Group, alkylsulfonyl-NR₃-Moto, ant
Sulfonyl-NR₃-Group, alkylsulfenyl group,
Rukylsulfinyl group, alkylsulfonyl group or R
_FiveSubstituted by a group); or C_1-6Alkyl group
(This may be one or two aryl groups; or heteroaryl
Reel base, R₆OCO-group, (R₃)₂NCO group, R_FiveCO-based, R₃O-CO
-Alkylene-NR₃-CO- group, (R₃)₂N-CO-alkylene-NR₃-C
O-group or R_FiveCO- Alkylene-NR₃-CO- group (in the formula, R₃
And R_FiveIs as defined above, and R₆Is water
Elementary atom, C_1-6Alkyl group, C_5-7Cycloalkyl group or
Represents an aralkyl group) which is substituted) by Y) Y is a NO group, a nitrogen atom or optionally an alkyl-substituted group.
Represents a methine group which may be₁, Z₂, Z₃as well as
Z_Four(These may be the same or different
May also be a methine group, carbon atom, imino group or nitrogen atom.
Represents a child and is a group Z₁~ Z_FourAt least one of the carbon atoms
Must be included, and one or two adjacent to the nitrogen atom
Methine groups may be substituted by carbonyl groups
I, Z_FiveAnd Z₆Each represents a carbon atom, or a group Z_Five
Or Z₆One of the groups represents a nitrogen atom, and the group Z_FiveAlso
Is Z₆Another group of represents a carbon atom, A is a cyano group;
No group; straight or branched C_1-4Aminoalkyl group; amidino
A group, a guanidino group or a guanidinoalkyl group,
The above amino group, aminoalkyl group, amidino group, guar
In the nidino or guanidinoalkyl group, the nitrogen source
One or two hydrogen atoms in one child is 1 or 2
C_1-4Optionally substituted by an alkyl group, or
Hydrogen atom is C_2-5(Alkoxycarbonyl) group; C_4-6(A
Lucenyloxycarbonyl) group; C_2-5(Alkyl carbo
Nyl) group; arylcarbonyl group, aryloxycal
Bonyl group, aralkoxycarbonyl group, alkanoyl group
Xymethoxy-carbonyl group, cycloalkanoyloxy
Cimethoxycarbonyl group, aralkanoyloxymethoxy
Sicarbonyl group, aroyloxymethoxycarbonyl
Group, phosphono group, dialkylphosphoryl group or O-a group
Alkyl-phosphono groups may be substituted,
The canoyl portions may each contain from 2 to 7 carbon atoms
In addition, the cycloalkanoyl moiety has a total of 4 to 8
It may contain carbon atoms and the methoxy moiety is C_3-6Shiku
Roalkyl group; aralkyl group, aryl group or aralkyl group
A alkyl group; or substituted by two alkyl groups
Also, these are also 5-membered rings with methylene carbon atoms.
Alternatively, a 6-membered ring may be formed, or B is 4 to 7
When a cyclic imine having a ring member of
Elementary atoms or alkyl groups (each of which is attached to an imino nitrogen
B), and B is a phenylene group (
This is a fluorine atom, chlorine atom or bromine atom; alkyl
Group, hydroxy group, alkoxy group, alkylsulfenyl
Group, alkylsulfinyl group, alkylsulfonyl
Group, nitro group, amino group, alkylamino group, dialky
Luamino group, alkylcarbonylamino group, alkyls
Fluoronylamino group or trifluoromethyl group
It may be substituted or disubstituted, and these substituents are
May be the same or different, at the same time
One or two methine groups in the above phenylene group is 1
Optionally substituted by 1 or 2 nitrogen atoms)
Or B is C_3-7Cycloalkylene group (4 members or
Is a 5-membered cycloalkylene ring and one ring member is a nitrogen atom.
May represent a child, and is also a 6- or 7-membered cycloalkyl
In the len ring, one or two ring members each represent a nitrogen atom.
At the same time, the bond to the carbon atom of the adjacent group is
Such as optionally present nitrogen atoms),
Indanylene group or 1,2,3,4-tetrahydrona
A butylene group (its saturated ring is bound to the group A and
The aromatic ring is attached to a group C or a fused 5-membered heterocyclic group
Represents a bond, C is a bond, an alkylene group, an arylene group,
-O-alkylene group, -S-alkylene group, -NH-a
Ruylene group, -N (alkyl) -alkylene group, -ar
Xylene-NH- group, -alkylene-N (alkyl)-
Group, -SO-alkylene group or -SO₂-Alkylene
Represents a group, D represents a bond or an alkylene group, and E represents C
_1-7Alkylene groups, each having 2 to 7 carbon atoms
Represents a rukenylene group or an alkynylene group, the double bond
Compound or triple bond is -Z₁-Z₂-Z₃-Z_Four-To the base nitrogen atom
May not be directly bonded, or E may be -Z₁-Z
₂-Z₃-Z_Four-If not directly attached to the nitrogen atom of the group
Is E is -O- group, -S- group, -SO- group, -SO₂−
Group, -NR₃-Group, -N (COR_Four)-Group, -CO- group, -NR₃-C
O-group, -CO-NR₃-Group, -SO₂-NR₃-Group, alkylsulfonyl
Imino group or arylsulfonylimino group (in the formula, R
₃And R_FourIs as defined above), or C
_4-7It may represent a cycloalkylene group, which may be 4-membered or 5-membered.
Member of the cycloalkylene ring, one ring member has a nitrogen atom
May represent, 6-membered or 7-membered cycloalkylene
In the ring, one or two ring members each represent a nitrogen atom
The methylene group adjacent to the nitrogen atom may be
May be substituted by a group, and at the same time the carbon of the adjacent group
Bonding to an atom is through any nitrogen atom present.
F may be a bond, straight chain or branched C_1-6Arche
Group, straight or branched having 2 to 6 carbon atoms each
Alkenylene or alkynylene groups (including their double bonds
Or triple bond is directly with the heteroatom or triple bond of group E
They may not be adjacent to each other, and the above alkylene group,
The rukenylene group and the alkynylene group are an aryl group and -C, respectively.
OOR₆Group, -CON (R₃)₂Or-CO-N (R₃) -Alkyl group (formula
Medium, R₃And R₆Is as defined above)
May be substituted, and -CO-N (R₃) -Alkyl group
Alkyl moiety (which may contain from 1 to 6 carbon atoms
I) is a radical R₇And R₈May be replaced by
R₇And R₈(These may be the same, and
May be different) are hydrogen atom, aryl group or
Is-COOR₆Group (in the formula, R₆Is as defined above
4) in each cycloalkylene moiety.
A cycloalkylene group having a carbon atom of alkylene-
Cycloalkylene group or cycloalkylene-alkyle
Group (CH group in the ring is replaced by a nitrogen atom)
And the bond to the adjacent group E is via a nitrogen atom.
May be bonded via the carbon atom of group E
In addition, D represents a bond and E represents an oxygen atom.
And F is an alkyl group, A is phenyl
An amino or acylamino group attached directly to the ring
And at the same time X is a sulfur atom and Y is nitrogen.
When it is an atom, the group ABC is 4-acetamino.
-Which may not be a piperazino group), and G is a group E
Represents a carbonyl group not attached to a heteroatom,
Is a hydroxy group; 3-4 carbons in the alkenyl moiety
Arylalkenyloxy group having an elementary atom; C_1-8Al
Coxy group (C_1-5Alkoxy groups are replaced by aryl groups
Optionally, or having 1 to 3 carbon atoms
Alkoxy groups are heteroaryl at the 1, 2 or 3 positions
Group or cycloalkyl group having 4 to 8 carbon atoms
May be substituted by, or the 2- or 3-position
And a pyrrolidin-2-one-1-yl group, a morpholino group,
Thiomorpholino group or 1-oxide-thiomorpholino
May be substituted by a group); if necessary 1 to
C optionally substituted by 3 alkyl groups_4-8Shiku
Ralkoxy group; benzocycloalkoxy group, benzosi
Chloroalkyl-alkoxy group, bicycloalkoxy group
Or bicycloalkylalkoxy group (cycloalkyl part
Having 4 to 8 carbon atoms in the minute,
Has 6 to 8 carbon atoms in the moiety, and if necessary
Optionally substituted by 1 to 3 methyl groups);
Has a total of 2 to 7 carbon atoms in the alkanoyl moiety
Alkanoyloxymethoxy group; cycloalkanoyl moiety
Cycloalkano having a total of 4 to 8 carbon atoms in the minute
Yloxy-methoxy group; 1-6 in the alkyl moiety
Alkoxycarbonyloxymethoxy having carbon atoms
A group; or 3 to 7 carbon atoms in the cycloalkyl moiety
With cycloalkoxycarbonyloxymethoxy
Group; aroyloxymethoxy group, aralkanoyloxy
Methoxy group, aryloxycarbonyloxymethoxy
Group or aralkoxycarbonyloxymethoxy group
(The methoxy part in each case is C_1-6Alkyl group, C_3-7Shi
Chloroalkyl group, or aralkyl group or aryl
Optionally substituted by a group)
Or G is a sulfo group, a phosphono group, an O-alkyl group
A group of phosphono groups or tetrazol-5-yl groups
Unless otherwise stated, the alkyl moiety,
The xylene or alkoxy part has 1 to 3 carbons, respectively.
May contain atoms, and the term "aryl group"
Is a fluorine atom, chlorine atom, bromine atom or
Is an iodine atom; or an alkyl group, trifluoromethyl
Group, nitro group, amino group, alkylamino group, dialky
Luamino group, alkanoylamino group, alkylsulfoni
Ruamino group, aminosulfonyl group, alkylaminosulfur
Honyl group, dialkylaminosulfonyl group, hydroxy
Group, alkoxy group, aralkoxy group, carboxy group,
Lucoxycarbonyl group, aminocarbonyl group, alkyl
Aminocarbonyl group, dialkylaminocarbonyl group,
Alkylsulfenyl group, alkylsulfinyl group
Or mono-, di- or
A phenyl group which may be trisubstituted (these substituents are
May be the same or different), or
Represents a naphthyl group and is referred to as a "heteroaryl group".
The term is a 5-membered heteroaromatic ring (this is an imino group; oxygen
Atom or sulfur atom; 1 to 2 nitrogen atoms and oxygen atoms
Or sulfur atom; or imino group and 1 to 3 nitrogen atoms
, Or a 6-membered heteroaromatic ring (which is 1, 2
Or 3 nitrogen atoms), and
The phenyl ring may be fused and the above ring may be fused.
Fluorine atom, chlorine atom or bromine atom; alkyl group, a
Lucoxy group, hydroxy group, amino group, dialkylamido
Group, alkylcarbonylamino group, alkylsulfoni
Luamino group or trifluoromethyl group; or C_1-4
Mono- or di-substituted with an alkylamino group
Good 2. R ₁ is a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom; an alkoxycarbonylamino group having 1 to 4 carbon atoms in the alkoxy moiety or an N-alkoxycarbonyl-alkylamino group; an alkyl group,
Hydroxy group, alkoxy group, phenylalkoxy group,
Represents an amino group, an alkylamino group, a dialkylamino group, a pyrrolidino group, a piperidino group, an alkylcarbonylamino group or an alkylsulfonylamino group, and unless otherwise specified, each alkyl moiety and alkoxy moiety has 1 to 3 carbon atoms. The alkyl moiety of the alkylamino group and the dialkylamino group may be substituted with a carboxy group or an alkoxycarbonyl group having 1 to 3 carbon atoms in the alkyl moiety, and X is an oxygen atom or sulfur. Atom or nitrogen atom or -NR ₂
Represents a group (wherein R ₂ is a hydrogen atom; straight chain or branched C
_1-14 alkyl group; alkenyl group or alkynyl group having 3 or 4 carbon atoms, respectively (the double bond or triple bond thereof may not be directly adjacent to the nitrogen atom); C _1-5 alkyl group [This is a carboxy group, an alkoxycarbonyl group, an aminocarbonyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, a phenylalkylaminocarbonyl group, a pyrrolidinocarbonyl group, a carboxyalkylaminocarbonyl group, an alkoxycarbonylalkylaminocarbonyl group, 2- Or a 4-imidazolyl group or a pyridyl group; a piperidinocarbonyl group (the 4-position methylene group is an oxygen atom, a sulfenyl group, a sulfinyl group, a sulfonyl group, an imino group,
An alkylimino group or a phenylalkylimino group may be substituted); or a phenyl group (optionally a chlorine atom or a bromine atom; or an amino group, a hydroxy group, an alkoxy group or an alkyl group; or 2
Number of which may be substituted by may be) optionally mono- or disubstituted by phenyl group]; C _3-7 cycloalkyl group; a pyridyl group; required by fluorine atom, a chlorine atom or a bromine atom or an alkyl group, Represents a phenyl group which may be mono- or di-substituted by an alkoxy group, an alkylsulfenyl group, an alkylsulfinyl group or an alkylsulfonyl group (these substituents may be the same or different) , Or R
₂ is a C _2-4 alkyl group (which is a 2-, 3- or 4-position hydroxy group, an alkoxy group, an alkylsulfenyl group,
Alkylsulfinyl group, alkylsulfonyl group, 1-
It is substituted with an imidazolyl group, a pyrrolidino group or a piperidino group, and the methylene group at the 4-position is an oxygen atom, a sulfenyl group, a sulfinyl group, a sulfonyl group,
Represents an imino group, an alkylimino group or a phenylalkylimino group), or R
₂ represents a C _2-6 alkyl group substituted with an amino group, an alkylamino group or a dialkylamino group at the 2-position, 3-position, 4-position, 5-position or 6-position) Unless otherwise specified, the above alkyl moiety And an alkoxy moiety may each contain 1 to 3 carbon atoms, Y represents a NO group, a nitrogen atom or a methine group optionally substituted by a C _1-3 alkyl group, Z ₁ , Z ₂ , Z ₃ and Z ₄ (which may be the same or different) are methine groups, carbon atoms,
It represents an imino group or a nitrogen atom, at least one of the groups Z _{1 to} Z ₄ must contain a carbon atom, and one or two methine groups adjacent to the nitrogen atom may be substituted with a carbonyl group. Well, Z ₅ and Z ₆ each represent a carbon atom, or one of the groups Z ₅ or Z ₆ represents a nitrogen atom, and the group Z ₅ or Z
₆ another group represents a carbon atom, A represents a cyano group; an amino group; a linear or branched C _1-4 aminoalkyl group; an amidino group, a guanidino group or a guanidinoalkyl group, and the above amino group, amino In an alkyl group, amidino group, guanidino group or guanidinoalkyl group, one of its nitrogen atoms has a hydrogen atom as a C _1-4 alkyl group; C _2-5 (alkoxycarbonyl) group; phenylalkoxycarbonyl group, phenyloxycarbonyl An oxy group or a benzoyl group; or an alkanoyloxymethoxycarbonyl group (the alkanoyl portion of which is 2 to
May contain 4 carbon atoms); or a phosphono group,
A may be substituted by a dialkylphosphoryl group or an O-alkyl-phosphono group, or when B represents a cyclic imine, A is also a hydrogen atom or a C _1-3 alkyl group (each of which is an imino nitrogen). Are combined)
And B is a phenylene group (which is a fluorine atom, a chlorine atom or a bromine atom; an alkyl group, a hydroxy group, an alkoxy group, an alkylsulfenyl group, an alkylsulfinyl group, an alkylsulfonyl group, a nitro group, an amino group, It may be mono- or di-substituted by an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a trifluoromethyl group, and these substituents may be the same or different. And the alkyl and alkoxy moieties may each contain 1 to 3 carbon atoms), or B is a pyridinylene group or a cycloalkylene group having 3 to 6 carbon atoms; a piperidinylene group or a piperazinylene group. (These are also carbons of adjacent groups through the nitrogen atom. Which may be bonded to an elementary atom), an indanylene group or a 1,2,3,4-tetrahydronaphthylene group (the saturated ring of which is bonded to the group A, and the aromatic ring of which is the group C or a condensed 5-membered heterocyclic group). Bonded to a ring group), C is a bond, methylene group, ethylene group, phenylene group, O
-Methylene group, S-methylene group, SO-methylene group, S
Represents an O ₂ -methylene group or an N- (alkyl) methylene group (each of which is attached to the group B by a heteroatom), or a methylene-N (alkyl) -group, each alkyl moiety being 1 to 3 Carbon atoms, D represents a bond or a methylene group or an ethylene group, E represents a C _1-5 alkylene group, an alkenylene group or an alkynylene group having 3 to 5 carbon atoms, respectively, in which Double bond or triple bond cannot be directly bonded to the nitrogen atom of the Z ₁ -Z ₂ -Z ₃ -Z ₄ group, or E is Z ₁ -Z ₂ -Z ₃ -Z ₄
When the nitrogen atom of the group is not bonded directly, it -O- group, -S- group, -SO- group, -SO ₂ - group, -N
H-group, -N (alkyl) -group, -N (COalkyl)
- group, -CO- group, -NH-CO- group, -N (alkyl) -CO- group, -CO-NH- group, -CO-N (alkyl) - group, -SO ₂ -NH- group, It may represent a —SO ₂ —N (alkyl)-group or an alkylsulfonylimino group (each alkyl part may contain 1 to 3 carbon atoms), a cyclohexylene group, a piperidinylene group or a piperazinylene group. Further, the methylene group adjacent to the nitrogen atom may be substituted with a carbonyl group, and at the same time, the carbon atom of the adjacent group may be bonded via the nitrogen atom, F is a bond; C _1-4 alkylene A group [which is a phenyl group, a carboxy group, an alkoxycarbonyl group, a phenylalkoxycarbonyl group or an alkylaminocarbonyl group (wherein the alkylaminocarbonyl group is (Including 5 carbon atoms), a phenyl group, a hydroxyphenyl group, a methoxyphenyl group, a benzyloxyphenyl group, a carboxy group, an alkoxycarbonyl group or a phenylalkoxycarbonyl group, or another carboxy group, an alkoxycarbonyl group or Optionally substituted by phenylalkoxycarbonyl groups)]; cyclohexylene groups, cyclohexylene-alkylene groups having 1 to 3 carbon atoms in the alkyl, alkylene and alkoxy moieties respectively. Or an alkylene-cyclohexylene group; a piperidinylene group or a pyrrolidinylene group (these may also be bonded to the adjacent group E via a nitrogen atom, and when the bonding is carried out via the carbon atom of the group E,
Also, when D represents a bond, E represents an oxygen atom, and F is an alkyl group, A represents an amino group or an acylamino group directly bonded to the phenyl ring), and G Represents a carbonyl group which is not bonded to the heteroatom of the group E, which is a hydroxy group; a cinnamyloxy group; a C _1-6 alkoxy group (the C _1-5 alkoxy group may be substituted by a phenyl group. , Or a C _1-3 alkoxy group may be substituted at the 1-, 2- or 3-position with a naphthyl group, a C _5-6 cycloalkyl group, a pyridyl group, or at the 2- or 3-position, pyrrolidine-2- On-
1-yl group may be substituted); C _5-8 cycloalkoxy group; indanyloxy group, 1,2,3,4-
A tetrahydronaphthyloxy group; a bicycloheptyloxy group or a bicycloheptylmethoxy group (the bicycloheptyl group may be substituted by 1 to 3 methyl groups); having a total of 2 to 5 carbon atoms in the alkanoyl moiety An alkanoyloxymethoxy group; an alkoxycarbonyloxymethoxy group having 1 to 2 carbon atoms in the alkyl moiety; or 5 in the cycloalkyl moiety
Or 6 may be substituted by a cycloalkoxycarbonyloxymethoxy group having 6 carbon atoms (each methoxy moiety may be substituted by an alkyl group), or G may have 1 to 3 carbon atoms. Have O-
Fused 5 of the general formula I, which represents an alkylphosphono group or a sulfo group, a phosphono group or a tetrazol-5-yl group.
Membered heterocyclic compounds, tautomers, stereoisomers, mixtures thereof and salts thereof. 3. R₁But also hydrogen atom, fluorine atom, chlorine atom
Bromine atom; 1-3 carbons in each alkoxy moiety
Alkoxy group having elementary atom or phenylalkoxy
Groups; each having 1 to 4 carbon atoms in the alkoxy moiety
Alkoxycarbonylamino group or N-alkoxy
Carbonyl-methylamino group; methyl group, hydroxy
Group, amino group, methylamino group, dimethylamino group, N
-Carboxymethyl-amino group, N-carboxymethyl
-Methylamino group, N-methoxycarbonylmethyl-me
Cylamino group, acetylamino group, piperidino group or
Represents a methylsulfonylamino group, X represents an oxygen atom, a sulfur atom or a nitrogen atom, or -NR₂
Represents a group (in the formula, R₂Is a hydrogen atom; straight chain or branched C
_1-14Alkyl group; allyl group or propargyl group;
Ruboxy group, methoxycarbonyl group, ethoxycarbonyl group
Group, aminocarbonyl group, methylaminocarbonyl
Group, dimethylaminocarbonyl group, benzylaminocarb
Bonyl group, phenylethylaminocarbonyl group, carbo
Xymethylaminocarbonyl group, methoxycarbonyl
Tylaminocarbonyl group, or pyridyl group; or
C substituted by a piperidinocarbonyl group_1-3Alkyl
Represents a group, and the methylene group at the 4-position is an oxygen atom or a sulfone
Phenyl group, sulfinyl group, sulfonyl group, imino group
Or may be substituted with a benzylimino group,
Or R₂Is C_1-4Alkyl group (this is a bromine atom if necessary)
Or chlorine atom or amino group, hydroxy group, metho
Mono- or di-substituted by xy or methyl groups
Optionally substituted by a phenyl group, or
Which is substituted by two phenyl groups)
Or R₂Is C_3-6Cycloalkyl group; pyridyl group;
If necessary, chlorine atom, methyl group, methoxy group, methyl group
Rusulfenyl group, methylsulfinyl group or methyl
Sulfonyl group (these substituents may be the same
And may be different) by monosubstitution or biposition
Represents an optionally substituted phenyl group, or R₂Is C
_2-3An alkyl group (which is hydroxy at the 2 or 3 position
Group, methoxy group, methylsulfenyl group, methylsulf
Inyl group, methylsulfonyl group, imidazolyl group
Is substituted by a pyrrolidino group or a piperidino group
The methylene group at the 4-position is an oxygen atom or sulfenyl
Group, sulfinyl group, sulfonyl group, imino group or
(May be substituted by a benzylimino group)
Or R₂Is 2nd, 3rd, 4th, 5th or 6th
C substituted with an amino group_2-6Represents an alkyl group) Y is a NO group, a nitrogen atom or optionally substituted with methyl.
Represents an optionally present methine group, Z₁, Z₂, Z₃And Z_Four(These may be the same
And may be different) is a methine group, a carbon atom,
Represents an imino group or a nitrogen atom, and represents a group Z₁~ Z_FourLess
One of them must contain a carbon atom, and the nitrogen atom
Adjacent one or two methine groups are linked by a carbonyl group.
May be substituted, Z_FiveAnd Z₆Each represent a carbon atom, or the group Z_FiveAlso
Is Z₆One of the groups represents a nitrogen atom, and the group Z_FiveOr Z
₆Another group of represents a carbon atom, A is an amino group; straight chain or branched C_1-3Aminoalkyl group;
Amidino group, guanidino group or guanidinomethyl group
Represents the above amino group, aminoalkyl group, amidino
Group, a guanidino group or a guanidinomethyl group,
One of nitrogen atoms and hydrogen atom is C_1-4Alkyl group; total 2 to
An alkoxycarbonyl group having 5 carbon atoms;
Is a benzoyloxycarbonyl group, acetyloxymeth
Xycarbonyl group, dimethylphosphoryl group or diethyl
It may be substituted with a tylphosphoryl group, and B is a phenylene group (this may be a fluorine atom, a chlorine atom or
Is a bromine atom; or a methyl group, a hydroxy group or
Optionally substituted by toxy group); pyridinylene
Group or C_3-6Cycloalkylene group; indanirene group
Is a 1,2,3,4-tetrahydronaphthylene group (for each
The saturated ring is bound to the group A and the aromatic ring is
Is attached to group C or a fused 5-membered heterocyclic group);
Or piperidinylene group or piperazinylene group (this
Are also attached to the carbon atom of the adjacent group through the nitrogen atom.
C) represents a bond, a phenylene group or an O-methylene group, D represents a bond or a methylene group, and E represents C._3-5Alkylene group, C_3-5Represents an alkenylene group,
The double bond in is Z₁-Z₂-Z₃-Z_Four Directly to the nitrogen atom of the group
May not be bonded, or E may be -Z ₁-Z₂-Z
₃-Z_Four When not directly attached to the nitrogen atom of the group,
E is -O- group, -S- group, -SO- group, -SO₂-Base,
-NH- group, -N (methyl)-group, -N (acetyl)-
Group, -N (SO₂CH₃)-Group, -CO- group, -NH-CO- group,
-N (CH ₃ ) -CO- group, -CO-NH- group, -CO-
N (CH₃ ) -Group, -SO₂-NH- group or -SO₂−
N (CH₃ ) -Group, piperidinylene group, piperazinylene group
Or it may represent an oxo-piperazinylene group, which
These nitrogen atoms are also bound to carbon atoms of adjacent groups
Well, F is bound; C_1-4Alkylene group [this is a phenyl group, cal
Voxy group, methoxycarbonyl group, benzyloxycal
Bonyl group, phenylethylaminocarbonyl group, (meth
Xyphenyl) ethylaminocarbonyl group or alk
Ruaminocarbonyl group (its alkylaminocarbonyl
The group is an alkyl moiety (which contains 1 to 4 carbon atoms)
Among them, phenyl group, hydroxyphenyl group, methoxy group
Phenyl group, carboxy group or benzyloxycarbo
It may be substituted by a nyl group or may be further substituted.
By a ruboxy group or a benzyloxycarbonyl group
May be substituted))
]; Piperidinylene group or pyrrolidinylene group (this
In each of these, the bond is made via the nitrogen atom of the group E.
On the condition that it is bonded to the adjacent group E via a nitrogen atom.
Or a cyclohexylene group or
Represents a cyclohexylene-methylene group, and (D represents a bond.
, Where E represents an oxygen atom and F represents an alkyl group.
When A is an amino group directly attached to the phenyl ring or
Is not an acylamino group), G is a carbonyl group not bound to the heteroatom of group E
Represents a hydroxy group; C_1-6Alkoxy group
It may be substituted by phenyl groups at positions 1-5
Or a cyclohexyl group at the 1- or 2-position, naphth
It may be substituted by a tyl group or a pyridyl group
Or a pyrrolidin-2-one-1-yl group at the 2-position,
Cinnamyloxy group, C_6-8Positioned by cycloalkoxy group
May be substituted); indanyloxy group, norbol
Nyloxy group or norbornylmethyloxy group; ar
An alkane having a total of 2 to 5 carbon atoms in the canoyl moiety
Canoyloxymethoxy group; 1-3 in the alkoxy part
Alkoxycarbonyl oxymeth having 1 carbon atom
Xy group; or cyclohexyloxy-carbonyloxy
It may be substituted with a simethoxy group, and
The moiety may be substituted by a methyl group, or
G is also a sulfo group, a phosphono group, an O-methyl-phosphono group
Or may represent a tetrazol-5-yl group, generally
Fused 5-membered heterocyclic compounds of formula I, their tautomers, stereoisomers
Isomers, mixtures thereof and salts thereof. 4. R ₁ is a hydrogen atom, a methyl group, a methoxy group, a methylamino group, a dimethylamino group, an N-butyloxycarbonyl-methylamino group, an N-isobutyloxycarbonyl-methylamino group or an N-carboxymethyl-group. Amino group, N-carboxymethyl-methylamino group,
N-methoxycarbonylmethyl-amino group or N-
A methoxycarbonylmethyl-methylamino group, X is an oxygen atom or a nitrogen atom, or a -NR ₂ group,
[Wherein R ₂ is a hydrogen atom; a linear or branched C _1-14 alkyl group; a C _1-3 alkyl group (which is substituted with a carboxy group or a methoxycarbonyl group); a C _1-4 alkyl group (This is optionally substituted by a phenyl group which may be mono- or di-substituted by a bromine atom, an amino group or a methoxy group, or by two phenyl groups or a pyridyl group); Or substituted at position 3 by an amino group or a piperidino group
A C _2-3 alkyl group (the methylene group at the 4-position thereof is substituted with an imino group, a benzylimino group, a sulfenyl group, a sulfinyl group or a sulfonyl group)] Y represents a NO group, a nitrogen atom or a methine group Represents Z ₁ , Z ₂ , Z ₃ and Z ₄ (these may be the same or different), a methine group, a carbon atom,
Represents an imino group or a nitrogen atom, at least two of the groups Z _{1 to} Z ₄ must contain carbon atoms, and one or two methine groups adjacent to the nitrogen atom are each substituted by a carbonyl group. Alternatively, Z ₅ and Z ₆ each represent a carbon atom, or one of the groups Z ₅ or Z ₆ represents a nitrogen atom, and the group Z ₅ or Z
Another group of ₆ represents a carbon atom, A represents an aminomethyl group or an amidino group, one of the nitrogen atoms of which a hydrogen atom may be replaced by a methoxycarbonyl group, and B represents a phenylene group, C represents a bond or an O-methylene group, D represents a bond, E represents a C _3-4 alkylene group, or E represents -Z ₁ -Z _2-.
When it is not directly bonded to the nitrogen atom of the Z ₃ -Z ₄ group, E is —O— group, —NH—CO— group or —CO—N.
H-group may be represented, F represents a bond or a C _1-3 alkylene group, and G represents a carboxy group, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a cyclohexyloxy group, a general formula Fused 5-membered heterocyclic compounds of I, tautomers thereof, stereoisomers including mixtures thereof, and salts thereof. 5. (a) 2- (4-amidino-phenyl) -5
-[(2-carboxy-ethyl) -aminocarbonyl]
-1-Methyl-benzimidazole, (b) 2- (4-amidino-phenyl) -1-benzyl-5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole, (c) 2- (4 -Amidino-phenyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1- (3-thiomorpholino-propyl) -benzimidazole, (d) 2- (4-amidino-phenyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1- [3- (S-oxide-thiomorpholino) -propyl] -benzimidazole, (e) 2- (4-amidino-
Phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [3- (S, S-dioxide-thiomorpholino) -propyl] -benzimidazole,
(f) 2- (4-amidino-phenyl) -1- (3-amino-propyl) -5-[(2-carboxyethyl) -aminocarbonyl] -benzimidazole, (g) 2- (4
-Amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1-methyl-benzimidazole-3-oxide, (h) 2- (4-amidino-phenyl) -1- [2- (4-benzyl-piperazino)-
Ethyl] -5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole, (i) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1 -Methyl-6-methylamino-benzimidazole, (j) 2- (4-amidino-
Phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -6- (N-carboxymethyl-methylamino) -1-methyl-benzimidazole, (k) 2-
(4-Amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (2-piperazino-ethyl) -benzimidazole, (l) 2- (4-amidino-phenyl) -5 -[(2-carboxy-ethyl) -aminocarbonyl] -1- [2- (3,4-dimethoxy-phenyl) -ethyl] -benzimidazole,
(m) 2- (4-amidino-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- (3-
Pyridylmethyl) -benzimidazole, (n) 2- (4
-Aminomethyl-phenyl) -5-[(2-carboxy-ethyl) -aminocarbonyl] -1- [2- (3,4
-Dimethoxy-phenyl) -ethyl] -benzimidazole, (o) 2- (4-amidino-phenyl) -5-
[(2-Carboxy-ethyl) -aminocarbonyl]-
1- (4-phenyl-butyl) -benzimidazole,
(p) 2- (4-amidino-phenyl) -1- [2- (4
-Amino-3,5-dibromo-phenyl) -ethyl]-
5-[(2-carboxy-ethyl) -aminocarbonyl] -benzimidazole, (q) 2- (4-amidino-
Phenyl) -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -1-methyl-benzimidazole, (r) 2- (4-amidino-phenyl) -5-
[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1- (3-thiomorpholino-propyl) -benzimidazole, (s) 2- (4-amidino-phenyl)
-5-[(2-Methoxycarbonyl-ethyl) -aminocarbonyl] -1- (4-phenyl-butyl) -benzimidazole, (t) 2- (4-amidino-phenyl)-
1- [2- (4-amino-3,5-dibromo-phenyl) -ethyl] -5-[(2-methoxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole,
(u) 2- (4-amidino-phenyl) -1- [2-
(3,4-Dimethoxy-phenyl) -ethyl] -5-
[(2-Isopropyloxycarbonyl-ethyl) -aminocarbonyl] -benzimidazole (v) 8- (4-
Amidino-phenyl) -1- (4-carboxy-butyl) -3,9-dimethyl-xanthine and (w) 2- (4
-Amidino-phenyl) -6-[(2-carboxy-ethyl) -aminocarbonyl] -3-methyl-imidazo [4,5-b] pyridine, a fused 5-membered heterocyclic compound of general formula I Mutants, stereoisomers, and salts thereof. 6. A physiologically acceptable salt of the compound according to at least one of claims 1 to 5 and an inorganic or organic acid or base. 7. One or more inert carriers and / or if necessary
Alternatively, a pharmaceutical composition comprising a compound according to at least one of claims 1 to 5 or a physiologically acceptable salt according to claim 6 together with a diluent. 8. At least one of claims 1 to 6 for preparing a pharmaceutical composition suitable for treating or preventing a disease in which large and small cell aggregates are generated or a disease in which cell-matrix interaction is involved. Use of the described compounds. 9. A compound according to claim 7, wherein the compound according to at least one of claims 1 to 6 is incorporated into one or more inert carriers and / or diluents by a non-chemical method. A method for preparing a pharmaceutical composition. 10. To prepare a) a compound of general formula I in which G represents a carboxyl group, a compound of the general formula: Where A to F, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5 and G ′ (which is attached to a carbon atom) is A compound of general formula I in which G represents a carboxyl group, or a compound of general formula I in which G represents a carboxyl group. To prepare imidazole, the general formula: (In the formula, A to G, R ₁ , R ₂ and Z _{1 to} Z ₄ are defined in Claim 1
A compound of general formula I, which is as defined in 5 to 5 and wherein Y ₁ represents a compound of A), or c) A represents an amidino group optionally substituted by an alkyl group. To prepare a general formula which may optionally be produced in the reaction mixture: (Wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, and X ₁ is an alkoxy group, an aralkoxy group, an alkylthio group or an aralkylthio group. or an amino group) of a compound of the general _{formula: R a -NH 2 (V)} ( wherein, the R _a represents a hydrogen atom or a C _1-4 alkyl group)
For the preparation of compounds of general formula I in which d) A represents an aminoalkyl group, by reacting with an amine of Reducing compounds of formula (wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5 and A ₁ represents a cyano group or cyanoalkyl) Or e) to prepare a compound of general formula I containing a sulfinyl or sulfonyl group not attached to the nitrogen atom,
General formula: (In the formula, A to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, provided that the groups R ₁ , B, C, E,
Or at least one of G or X contains a sulfenyl group or a sulfinyl group which is not bonded to a nitrogen atom), or f) A is an alkoxy having a total of 2 to 5 carbon atoms. A carbonyl group, an arylmethoxycarbonyl group, an arylethoxycarbonyl group, an aryloxycarbonyl group, an alkylcarbonyl group, an amino group substituted with an aralkylcarbonyl group or an arylcarbonyl group, an aminoalkyl group, an amidino group, a guanidino group or a guanidinoalkyl group, To prepare compounds of the general formula I, which have the general formula: (Wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, and A ₂ is an amino group, an aminoalkyl group, an amidino group, a guanidino group. Or a guanidinoalkyl group) is represented by the general formula: X ₂ —COR _b (IX) (wherein R _b is a C _1-4 alkoxy group, an arylmethoxy group, an arylethoxy group, an aryloxy group, an alkyl group, An aralkyl group or an aryl group, and X ₂ represents a nucleophilic leaving group) or g) G represents a carbonyl group which is not bonded to the heteroatom of the group E. Is a cinnamyloxy group; a C _1-6 alkoxy group (the C _1-5 alkoxy group may be substituted by a phenyl group, or the C _1-3 alkoxy group is a naphthyl group at the 1-, 2- or 3-position, Substituted by C _5-6 cycloalkyl group, pyridyl group May be listed, or 2nd or 3rd
Optionally substituted by a pyrrolidin-2-one-1-yl group at the position), a C _5-8 cycloalkoxy group, an indanyloxy group, a 1,2,3,4-tetrahydronaphthyloxy group, a bicycloheptyloxy group. Group or bicycloheptylmethoxy group, alkanoyloxymethoxy group having a total of 2 to 5 carbon atoms in the alkanoyl moiety, alkoxycarbonyloxymethoxy group having 1 to 2 carbon atoms in the alkyl moiety, or cycloalkyl moiety To prepare a compound of general formula I which is optionally substituted by a cycloalkoxycarbonyloxymethoxy group having 5 or 6 carbon atoms, the methoxy moiety of which may in each case be substituted by an alkyl group,
General formula: Wherein A to F, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, and G ″ represents a carboxy group or an alkoxycarbonyl group. General formula: X ₃ -R _c (XI) (In the formula, X ₃ represents a hydroxy group or a nucleophilic leaving group, and R _c represents a cinnamyloxy group; a C _1-6 alkyl group (C _1-5 The alkyl group may be substituted with a phenyl group, or the C _1-3 alkyl group may be substituted with a naphthyl group, a C _5-6 cycloalkyl group or a pyridyl group at the 1-position, 2-position or 3-position. , Or optionally substituted by a pyrrolidin-2-one-1-yl group at the 2- or 3-position), a C _5-8 cycloalkyl group, an indanyl group, 1,
2,3,4-tetrahydronaphthyl group, bicycloheptyl group or bicycloheptylmethyl group, alkanoyloxymethyl group having a total of 2 to 5 carbon atoms in the alkanoyl moiety, and 1 to 2 carbon atoms in the alkyl moiety Represents an alkoxycarbonyloxymethyl group having or a cycloalkoxycarbonyloxymethyl group having 5 or 6 carbon atoms in the cycloalkyl moiety, each methyl moiety of which may be substituted by an alkyl group) Or h) to prepare a compound of general formula I wherein A represents an amidino group attached to the nitrogen atom of a guanidinoalkyl group or a cyclic imino group, (Wherein B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, and A ₃ represents an aminoalkyl group), or a general formula : [Chemical formula 10] (In the formula, B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, provided that the group B contains a cyclic imino group). To prepare a compound of general formula I in which i) A represents a guanidino group attached to the aromatic ring, the compound of general formula: (In the formula, B to G, R ₁ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5, provided that B represents an aromatic ring or a heteroaromatic ring. As a condition and A ₄
Represents an amino group), or j) to prepare a compound of general formula I in which D represents a bond and E represents a —NR ₃ —CO— group. , The general formula: (Wherein A to C, R ₁ , R ₃ , Z _{1 to} Z ₆ , X and Y are as defined in claims 1 to 5), the compound of the general formula: X ₄ —CO—F— G (XVI), wherein F and G are as defined in claims 1 to 5 and X ₄ represents a nucleophilic leaving group, or a reactive derivative thereof, or k) a general formula I in which A represents an amino group or an aminoalkyl group
To prepare compounds of the general formula: (Wherein R ₁ , BG, X, Y and Z _{1 to} Z ₆ are as defined in claims 1 to 5, and A ₅ is H ₂ N-.
A compound having a CO-T group (wherein T represents a bond or a C _1-4 alkylene group) is represented by the general formula: (Wherein R ₉ represents an acyl group of an organic carboxylic acid) is reacted with a phenyliodo (III) compound, or l) A is an aminoalkyl group (the amino group is not bound to a quaternary carbon atom) , Or an amino group, which is attached to the CH or CH ₂ group of group B or C, to prepare a compound of the general formula: (Wherein R ₁ , BG, X, Y and Z _{1 to} Z ₆ are as defined in claims 1 to 5, and A ₆ is a hydroxyimino group or 1 to 4 carbon atoms. Representing a hydroxyiminoalkyl group having), or m) A is an amino group substituted by a dialkylphosphoryl group having 1 to 3 carbon atoms in the alkyl moiety, respectively.
To prepare compounds of general formula I which represent an aminoalkyl group, an amidino group, a guanidino group or a guanidinoalkyl group, a compound of the general formula: (Wherein R ₁ , BG, X, Y and Z _{1 to} Z ₆ are as defined in claims 1 to 5, and A ₇ is an amino group, a straight chain or a branched C _1-4. Aminoalkyl group, amidino group, guanidino group or a guanidinoalkyl group having 1 to 3 carbon atoms in the alkyl moiety is represented by the formula: X ₅ —PO (OR ₁₀ ) ₂ (XXI) (wherein , R ₁₀ represents a C _1-3 alkyl group, and X ₅ represents a nucleophilic leaving group group), or n) the general formula I in which E represents a —CO—NR ₃ — group. For the preparation of compounds of the general formula: (In the formulas, A to D, X, Y, and Z _{1 to} Z ₆ are defined in claims 1 to 5.
A compound of general formula in which) as defined _{in: HNR 3 -F-G (XXIII} ) ( wherein, F, and compounds of the G and R ₃ are as defined in claim 1 to 5) React and, if desired,
A compound of the general formula I thus obtained, wherein R ₁ is
5 represents one of the amino groups or aminoalkyl groups described in 5) is converted by alkylation into the corresponding alkylamino or dialkylamino compounds of the general formula I and, if necessary, for protecting the reactive groups. The protecting groups used in the reaction are then cleaved off and / or the compound of general formula I thus obtained is optionally resolved into its stereoisomer and / or the general formula thus obtained 7. Cyclics according to claims 1 to 6, characterized in that the compounds of I are converted into their salts, more particularly into their physiologically acceptable salts with inorganic or organic acids or bases for pharmaceutical use. Method for preparing imino derivative.